Levocetirizine and montelukast in the treatment of inflammation mediated conditions

ABSTRACT

The embodiments described herein include methods and formulations for treating viruses and diseases that are exacerbated by inflammatory responses in the body. The methods and formulations include, but are not limited to, methods and formulations for delivering effective concentrations of levocetirizine and montelukast to a patient in need. The methods and formulations can comprise conventional and/or modified-release elements, providing for drug delivery to the patient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of PCT Patent Application No.PCT/US2015/049767, filed Sep. 11, 2015, which claims the benefit ofpriority to U.S. Provisional Patent Application No. 62/050,668, filedSep. 15, 2014. The foregoing applications are fully incorporated hereinby reference in their entireties for all purposes.

BACKGROUND

Field of the Invention

The disclosure generally relates to the field of treatment for viralinfection and disease using levocetirizine and montelukast.

Description of the Related Art

Several viruses are currently the focus of attention due to their severeacute symptoms and potential for mortality. For instance, Ebola viruselicits a highly lethal hemorrhagic fever for which there are currentlyno effective vaccines or countermeasures. Ebola also carries a high rateof mortality. West Nile infection, Dengue fever, and yellow fever,caused by mosquito-borne viruses, and tick-borne encephalitis (“TBE”), atick borne disease caused by the tick borne-encephalitis virus, causedebilitating and long lasting symptoms and, in some instances, also leadto mortality. Each of these viral infections carries a risk of prolongedsecondary issues resulting from the acute phase of the viral infection.Malaria, a parasitic infection, also mosquito-borne, also causesdebilitating and long lasting symptoms and, in some instances, leads tomortality. This parasitic infection carries a risk of prolongedsecondary issues resulting from the acute phase of the infection.

Alzheimer's disease, dementia, dementia with Lewy bodies, Parkinson's,Amyotrophic lateral sclerosis (ALS), frontotemporal dementia, andHuntington's disease are debilitating progressive neurological diseasesand disease states. These diseases and disease states currently areinadequately treated.

SUMMARY

Some embodiments described herein pertain to a method of treating apatient having an inflammation-mediated condition. In some embodiments,the method comprises administering to a patient an effective amount of acombination of levocetirizine and montelukast.

Some embodiments described herein pertain to a method of treating apatient having an NFκB-mediated condition. In some embodiments, themethod comprises administering to the patient an effective amount of acombination of levocetirizine and montelukast.

Any of the embodiments described above, or described elsewhere herein,can include one or more of the following features or steps. In someembodiments, the condition is a neurological disease.

In some embodiments, the condition treated by administering an effectiveamount of montelukast and levocetirizine is a condition selected fromthe group consisting of Alzheimer's disease, dementia, dementia withLewy bodies, Parkinson's, Amyotrophic lateral sclerosis, frontotemporaldementia, and Huntington's disease. In some embodiments, the conditionis one that is caused by a viral infection. In some embodiments, thecondition is caused by a virus selected from the group consisting of theEbola virus, the West Nile virus, the Dengue virus, the tickborne-encephalitis virus, and HIV. In some embodiments, the condition iscaused by a parasitic infection. In some embodiments, the parasiticinfection is caused by Malaria.

In some embodiments, the combination of levocetirizine and montelukastis administered in a sequential manner. In some embodiments, thecombination of levocetirizine and montelukast is administered in asubstantially simultaneous manner. In some embodiments, the combinationof levocetirizine and montelukast is administered to the patient by oneor more of the routes consisting of enteral, intravenous,intraperitoneal, inhalation, intramuscular, subcutaneous and oral. Insome embodiments, the levocetirizine and montelukast are administered bythe same route. In some embodiments, the levocetirizine and montelukastare administered via different routes. In some embodiments, one or moreof levocetirizine or montelukast are provided as a slow releasecomposition.

In some embodiments, the combination further comprises other medicationsknown for use in treating one of the listed conditions. In someembodiments, the combination further comprises a steroid.

Some embodiments pertain to methods of treating a patient having acondition selected from the group consisting of Alzheimer's disease,dementia, dementia with Lewy bodies, Parkinson's, Amyotrophic lateralsclerosis, frontotemporal dementia, and Huntington's disease. In someembodiments, the method comprises administering to the patient aneffective amount of a combination of levocetirizine and montelukast.

Some embodiments pertain to methods of treating a patient having acondition selected from the group consisting of Ebola virus, West Nilevirus, Dengue virus, tick-borne-encephalitis (TBE), and HIV. Someembodiments pertain to methods of treating a patient having Malaria. Insome embodiments, the method comprises administering to the patient aneffective amount of a combination of levocetirizine and montelukast.

Some embodiments pertain to methods of treating a patient having aninflammation-mediated condition. In some embodiments, the methodcomprises identifying a patient with an inflammation-mediated condition.In some embodiments, the method comprises administering to the patientan effective amount of a combination of levocetirizine and montelukast.

Some embodiments pertain to a combination of levocetirizine andmontelukast for use in the treatment of an inflammation-mediatedcondition.

Some embodiments pertain to a combination of levocetirizine andmontelukast for use in the treatment of a viral infection. In someembodiments, the viral infection selected from Ebola virus, West Nilevirus, Dengue virus, tick-borne encephalitis (TBE), or HIV. Someembodiments pertain to a combination of levocetirizine and montelukastfor use in the treatment of a parasitic infection. Some embodimentspertain to a combination of levocetirizine and montelukast for use inthe treatment of Malaria.

Some embodiments pertain to a combination of levocetirizine andmontelukast for use in the treatment of a neurodegenerative disease. Insome embodiments, the neurodegenerative disease is selected fromAlzheimer's disease, dementia, dementia with Lewy bodies, Parkinson's,Amyotrophic lateral sclerosis, frontotemporal dementia or Huntington'sdisease.

Some embodiments pertain to the use of a combination of levocetirizineand montelukast for the manufacture of a medicament for the treatment ofan inflammation-mediated condition, a viral infection or aneurodegenerative disease.

Some embodiments pertain to a method of treating a patient having anNFκB mediated condition is disclosed. In some embodiments, the methodcomprises administering to the patient an effective amount of acombination of levocetirizine and montelukast.

In some embodiments, a method is disclosed for treating a patient havinga condition caused by a virus selected from the group consisting ofEbola virus, West Nile virus, Dengue virus, tick-borne encephalitisvirus (TBE), and HIV. In some embodiments, the method comprisesadministering to the patient an effective amount of a combination oflevocetirizine and montelukast.

In some embodiments, a method is disclosed for treating a patient havinga condition caused by Malaria. In some embodiments, the method comprisesadministering to the patient an effective amount of a combination oflevocetirizine and montelukast.

In some embodiments, a method is disclosed for treating a patient havinga condition selected from the group consisting of Alzheimer's disease,dementia, dementia with Lewy bodies, Parkinson's, Amyotrophic lateralsclerosis, frontotemporal dementia, and Huntington's disease. In someembodiments, the method comprises administering to the patient aneffective amount of a combination of levocetirizine and montelukast.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic diagram illustrating an NF-kB mediated pathwayutilized by RNA viruses, Ebola and Dengue, in upregulating theinflammatory cascade.

FIG. 2 is a schematic diagram illustrating the actions of levocetirizineand montelukast in treating NF-kB mediated conditions.

DETAILED DESCRIPTION

Some examples described herein illustrate the use of levocetirizine andmontelukast as a medicament for the treatment of viruses and/ordiseases. In some embodiments, target viruses and diseases are thosethat are exacerbated by the inflammatory responses they produce in thebody. In some embodiments, by reducing the inflammatory responses theyelicit in the body, the viruses and diseases are treated. In someembodiments, the use of a combination of levocetirizine and montelukasttargets multiple inflammatory pathways in the body, decreasinginflammation and allowing treatment of viral infection and disease. Theexamples described herein are illustrative and not intended in any wayto restrict the general inventions presented and the various aspects andfeatures of these inventions. Furthermore, the phraseology andterminology used herein is for the purpose of description and should notbe regarded as limiting. No features or steps disclosed herein areessential or indispensable.

As used herein, “treatment” pertains to broadly to alleviating the acuteand/or long term effects of a virus or disease. Treatment may compriseone or more of slowing progression, shortening duration, decreasingpathogens associated with, alleviating or reducing the symptomsassociated with, decreasing the duration of symptoms associated with,and alleviating and/or decreasing long term or residual effects and/orsecondary issues associated with viral infection or disease.

Without being bound to any particular theory, it is believed that thecombination of levocetirizine and montelukast simultaneously blockmultiple overlapping and/or separate inflammatory pathways in the bodythereby effecting treatment of viruses or diseases (e.g.,neurodegenerative disease). It is believed that unchecked,pro-inflammatory reactions divert immune-competent cells in the body,detracting them from their otherwise beneficial anti-pathogenicfunctions. Exacerbating the problem, and in contrast to clearing thepathogen (e.g., virus or a misfolded protein) or reducing theinflammatory response, the activated cells instead release additionalpro-inflammatory mediators diverting immune-competent cells from theirroles in immune surveillance. These augmented inflammatory responsescontribute to the development and progression of the viral infection orneurodegenerative disease. In some embodiments, levocetirizine andmontelukast act by down regulating pro-inflammatory mediators elicitedby viruses or diseases allowing the body's own defenses to attackinvasive pathogens. In some embodiments, the levocetirizine andmontelukast additionally have anti-pathogenic effects that treat viralinfections and disease.

In some embodiments, the combination of levocetirizine and montelukastcan be used in methods to treat RNA viruses. In some embodiments, thecombination of levocetirizine and montelukast is used in a method totreat one or more viruses selected from the group consisting of Ebolavirus, West Nile infection, Dengue fever, Yellow Fever, TBE, and HIV. Insome embodiments, the methods of treating RNA viruses (or other viruses)with levocetirizine and montelukast achieve synergy by acting onmultiple inflammatory signaling pathways in the body. In someembodiments, the combination of levocetirizine and montelukast can beused in methods to treat parasitic infection. In some embodiments, thecombination of levocetirizine and montelukast is used in a method totreat Malaria.

In some embodiments, the combination of levocetirizine and montelukastcan be used in methods to treat one or more diseases (e.g.,neurodegenerative diseases). In some embodiments, the combination oflevocetirizine and montelukast are used in methods to treat one or morediseases selected from the group consisting of Alzheimer's disease,Parkinson's disease, multiple sclerosis, Amyotrophic lateral sclerosis,and Huntington's disease. In some embodiments, the combination oflevocetirizine and montelukast can be used in methods to treat dementia.

Levocetirizine is an antihistamine and montelukast is a leukotrienereceptor antagonist. Levocetirizine, as a potent H1-antihistamine, actsin part by down-regulating the H1 receptor on the surface of mast cellsand basophils to block the IgE-mediated release of histamine—the agentresponsible for the cardinal symptoms of innate immune responses,including fever, sneezing, rhinorrhea, nasal congestion, itchy palate,and itchy red and watery eyes. Levocetirizine even decreases certainviral titers in vitro by log-2 (e.g., rhinovirus). Montelukast, aleukotriene receptor antagonist, acts by binding with high affinity andselectivity to the CysLT1 receptor to inhibit the physiologic actions ofthe leukotriene LTD4 (see FIG. 2). Leukotrienes are fatty signalingmolecules whose effects include airway edema, smooth muscle contractionand altered cellular activity associated with the inflammatory process.Overproduction of leukotrienes is a significant contributor toinflammation in viral infection and neurodegenerative disease.

Levocetirizine and montelukast are in different drug classes and targetdifferent receptors in the body. Whereas they target different receptorsin the body, levocetirizine and montelukast can achieve their effect viadifferent molecular pathways. In some embodiments, the combination ofmontelukast and levocetirizine achieves synergy to shorten the course ofviral infection and disease by targeting these different pathways in thebody. In some embodiments, multiple inflammatory signaling pathways inthe body are targeted to achieve treatment of viral infection or diseasewith levocetirizine and montelukast. In some embodiments, synergy isachieved by downregulating certain inflammatory processes. In someembodiments, the use of the combination of montelukast andlevocetirizine decreases one or more of the symptoms of, the durationof, morbidity from, and mortality from viruses and inflammation-relateddiseases and viruses. In some embodiments, the combination oflevocetirizine and montelukast decreases the rate of virus and/ordisease progression. In some embodiments, the combined levocetirizineand montelukast therapy can improve quality of life by amelioratingsymptoms/side effects/the viral or disease process itself, resulting indecreased health-care costs. In some embodiments, a synergistic effectcan be observed in the use of a combination of levocetirizine andmontelukast to treat inflammation.

Without being bound to any particular theory, the effect of thecombination of levocetirizine and montelukast is due, at least in part,to the fact that both levocetirizine and montelukast affect eosinophilmigration/quantity; the eosinophil is considered byscientists/clinicians as one hallmark of inflammation. Additionally, asdiscussed elsewhere herein, the response may be related, at least inpart, due to levocetirizine's interference with the toll-like receptors(TLRs) and montelukast's separate interference with theleukotriene-related pathways to inflammation.

In some embodiments, the combination of levocetirizine and montelukastcan be used in methods to treat viruses and diseases that activate theimmune system via pathogen-associated molecular patterns (PAMPs). PAMPsare molecular structures carried on pathogens and that have beensubstantially conserved over time. PAMPs comprise glycoproteins,lipopolysaccharides, proteoglycans and nucleic acid motifs broadlyshared by microorganisms that are essential to their survival. BecausePAMPs have been evolutionarily conserved in nature, the mammalian innateimmune system has evolved to recognize them.

Immune recognition of these PAMPs is accomplished using encoded proteinpattern recognition receptors (PRRs). PRRs can be activated by pathogenssuch as viruses (e.g., RNA viruses), at which time they upregulate thetranscription of cytokines, chemokines, type I interferons (IFNs), andantimicrobial proteins. This upregulation initiates one or moreinflammation cascades that may interfere with the body's ability todefend against viruses. Triggered innate immune mechanisms are alsoemerging as a crucial component of major neurodegenerative diseases.Microglia and other cell types in the brain can be activated in responseto pathogens (e.g., misfolded proteins or aberrantly localized nucleicacids). This diverts microglia from their physiological and beneficialfunctions, and leads to their sustained release of pro-inflammatorymediators. Activation of innate immune signaling pathways—in particular,the NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome byaberrant host proteins can lead to the development of diverseneurodegenerative disorders. During chronic activation of microglia, thesustained exposure of neurons to pro-inflammatory mediators can causeneuronal dysfunction and contribute to cell death. Because chronicneuroinflammation is observed at relatively early stages ofneurodegenerative disease, targeting the mechanisms that drive thisprocess is useful for therapeutic purposes.

In some embodiments, the combination of levocetirizine and montelukasttreats viruses that activate the innate immune system by blockingcertain inflammatory responses. In some embodiments, the combination oflevocetirizine and montelukast can be used in methods to treat virusesthat activate the innate immune system via PRRs and/or that upregulatepro-inflammatory factors including one or more of cytokines, chemokines,and type I interferons (IFNs). In some embodiments, the combination oflevocetirizine and montelukast treat viruses that upregulate one or moreof cytokines, chemokines, type I interferons (IFNs), and antimicrobialproteins by decreasing inflammation associated with these viruses and/orby blocking upregulation of these pro-inflammatory factors. In someembodiments, the combination of levocetirizine and montelukast treatviruses by down regulating one or more of cytokines, chemokines, andtype I interferons (IFNs). In some embodiments, in addition todownregulating the above agents, the combination of levocetirizine andmontelukast act by decreasing viral titers.

In some embodiments, the combination of levocetirizine and montelukasttreats pathogens (e.g., misfolded proteins) that contribute toinflammation-related diseases (e.g., neurodegenerative diseases) thatactivate the innate immune system. In some embodiments, the combinationof levocetirizine and montelukast treat neurodegenerative disease byblocking certain inflammatory responses. In some embodiments, thecombination of levocetirizine and montelukast can be used in methods totreat diseases that progress through prolonged activation of the immunesystem (e.g., the adaptive as well as the innate immune system) viaPRRs. In some embodiments, the combination of levocetirizine andmontelukast treat neurodegenerative diseases by preventing theupregulation of one or more of cytokines, chemokines, and type Iinterferons (IFNs) and by decreasing inflammation associated with thesefactors. In some embodiments, the combination of levocetirizine andmontelukast down regulate one or more of cytokines, chemokines, and typeI interferons (IFNs) to treat neurodegenerative disease. In someembodiments, in addition to downregulating the above agents, thecombination of levocetirizine and montelukast contributes to a decreasein pathogens associated with neurodegenerative disease.

Toll-like receptors (TLRs) are a particular type of PRR that havesubstantial importance in the initiation of antiviral response uponinfection. In some embodiments, the combination of levocetirizine andmontelukast can be used in methods to treat viruses and/or disease byinterfering with the innate immune system signaling pathways thatoperate, at least in part, through TLRs. In some embodiments, thecombination of levocetirizine and montelukast treats viruses, such asRNA viruses, and neurodegenerative diseases that activate innate immunereceptors (such as RNA viruses or neurodegenerative diseases). In someembodiments, the combination of levocetirizine and montelukast treatsviruses and diseases that activate immune responses via TLRs byinterfering with TLR activation.

TLRs comprise of family with 10 members in humans (TLR1, TLR2, etc.).TLR2, TLR3, TLR4, TLR7 and TLR8 are of importance in recognizingstructural features of RNA viruses—both double-stranded andsingle-stranded—as well as surface glycoproteins. Table 1 belowdemonstrates some viral targets of TLRs for which the combination oflevocetirizine and montelukast are effective in treating:

TABLE 1 Individual TLRs and the RNA viruses recognized by them. ReceptorVirus Ligand TLR7 Influenza A virus ssRNA Vesicular stomatitis virusssRNA Human immunodeficiency ssRNA virus Dengue virus ssRNA Sendai virusssRNA Lactate dehydrogenase- ssRNA elevating virus Mouse mammary tumorvirus ssRNA Murine leukemia virus ssRNA TLR8 Human immunodeficiencyssRNA virus TLR3 Reoviridae dsRNA Respiratory syncytial virus dsRNA WestNile virus dsRNA Coxsackievirus B3 dsRNA Poliovirus dsRNA Influenza Avirus dsRNA Punta Toro virus dsRNA TLR2 Measles virus HA Lymphocytic ?choriomeningitis virus Hepatitis C virus Core protein/NS3 TLR4Respiratory syncytial virus Fusion protein Coxsackievirus B4 ? Mousemammary tumor virus Envelope protein Murine leukemia virus EnvelopeproteinThe TLR family is also involved in the recognition a broad range of RNAviruses as well as non-RNA viruses, fungi, parasites, and bacteria. Insome embodiments, the combination of levocetirizine and montelukasttreats inflammation-related disease where inflammation is propagated viaTLRs. In some embodiments, the combination of levocetirizine andmontelukast is used in methods to treat inflammation-related disease orviral infection by down regulating inflammation activated at least inpart through receptors consisting of the group consisting of TLR7, TLR8,TLR3, TLR2, TLR4, and combinations thereof.

A common feature of all TLR recognition is the activation of three majorsignaling pathways: nuclear factor kappa-light-chain-enhancer ofactivated B cells (NF-kB), mitogen-activated protein kinase (MAPKs), andone or more of the interferon regulatory factors (IRFs). In someembodiments, the combination of levocetirizine and montelukast is usedin methods to treat viruses and/or inflammation-related disease byblocking activation of one or more of these pathways.

NF-kB plays a pivotal role across a spectrum of inflammation, immunity,cell proliferation, differentiation, and survival. In some embodiments,the combination of levocetirizine and montelukast is used in methods totreat viruses and diseases that elicit cellular activity or inflammatoryresponses via NF-kB. In some embodiments, the combination oflevocetirizine and montelukast treats viruses and/orinflammation-related disease by blocking activation through the NF-kBpathway. In some embodiments, the combination of levocetirizine andmontelukast treats viruses and/or inflammation-related disease byblocking TLR activation through the NF-kB pathway and at least one othercellular signaling pathway selected from the group consisting of theMAPKs pathway and the IRFs pathway. In some embodiments, the combinationof levocetirizine and montelukast treats viruses and/orinflammation-related disease by blocking cellular signaling pathwaysother than those mediated by TLRs.

MAPKs active activator protein 1, together with NF-kB, induces theexpression of genes required for inflammatory responses (and foradaptive immune responses) including IL-1β, IL-6, IL-18, and tumornecrosis factor (TNF). In some embodiments, the combination oflevocetirizine and montelukast are used in methods to treats viruses anddisease in part through blocking activation of MAPK pathways. In someembodiments, the combination of levocetirizine and montelukast treatsviruses and disease by blocking or inhibiting the expression of one ormore of IL-1β, IL-6, IL-18, and tumor necrosis factor (TNF).

IFNs also play a central role in the induction of antiviral responsesand trigger transcription of IFN-inducible genes that influence proteinsynthesis, growth regulation, apoptosis, maturation of dendritic cells,cytotoxicity of natural killer cells, and differentiation ofvirus-specific cytotoxic T lymphocytes. IFNs are also linked toinflammatory responses related to viral infection and disease. In someembodiments, the combination of levocetirizine and montelukast treatsviruses and/or inflammation-related disease in part through blockingactivation of IRF and/or IFN pathways. IRF3 and IRF7 are essential forthe induction of the type I interferons (IFN). In some embodiments, thecombination of levocetirizine and montelukast treats viruses and/orinflammation-related disease in part through blocking activation of oneor more of IRF3 and IRF7.

Retinoic acid-inducible gene I (RIG-I) like receptors (RLRs) arecytosolic protein sensors expressed by most cells of the human organism.RLRs are critical sensors of viral infection in most cell types. Uponbinding to viral RNA structures produced during viral replication, tworepeats of a cysteine-aspartic protease (caspase)-recruiting domain(CARD)-like region at the N terminus are exposed. These then interactwith other CARD containing proteins to trigger downstream signalingevents. RLRs are typically found in low concentrations in the cell, but,once a virus is detected, they are upregulated in much greaterconcentrations. In some embodiments, the combination of levocetirizineand montelukast is used in methods to down regulate activation of RLRs.In some embodiments, the combination of levocetirizine and montelukastare used in methods to treat viruses in part by down regulating theactivation of RLRs.

RIG-I, as an RLR, is important in recognizing and initiating cytokineproduction in response to a wide range of viruses from many differentfamilies. These families include the Ebola Virus. Recognition isantagonized by the Ebola virus V35 protein, as the secreted V35 bindsthe dsRNA ligand preventing the activation of RIG-1 mediated signaling.Table 2, below, shows several RNA virus targets of RIG-I.

TABLE 2 Individual RLRs and the RNA viruses recognized by them ReceptorVirus Ligand RIG-I Sendai virus ss/dsRNA Newcastle disease virusss/dsRNA Respiratory syncytial virus ss/dsRNA Measles virus ss/dsRNANipah virus ss/dsRNA Vesicular stomatitis virus ss/dsRNA Rabies virusss/dsRNA Influenza A virus ss/dsRNA Influenza B virus ss/dsRNA Ebolavirus ss/dsRNA Lassa virus ss/dsRNA Lymphocytic choriomeningitis virusss/dsRNA Rift Valley fever virus ss/dsRNA Japanese encephalitis virusss/dsRNA Hepatitis C virus ss/dsRNA West Nile virus ss/dsRNA Denguevirus ss/dsRNA Rotavirus ss/dsRNA MDA5 Encephalomyocarditis virus dsRNATheiler's virus dsRNA Mengo virus dsRNA Rabies virus dsRNA West Nilevirus dsRNA Sendai virus dsRNA Dengue virus dsRNA Rotavirus dsRNA Murinehepatitis virus dsRNA Murine norovirus 1 dsRNAIn some embodiments, the combination of levocetirizine and montelukastis used in methods of blocking activation of inflammation via the RIG-Ipathway. In some embodiments, the combination of levocetirizine andmontelukast treats viruses (and/or neurological disease) by blockingactivation of the RIG-I pathway.

Melanoma differentiation-associated antigen 5 (MDA5) is structurallysimilar to RIG-I. It initiates cytokine and type I IFN production viaIPS-1 similarly to RIG-I and is important in initiating cytokineresponses to picornaviruses, including encephalomyocarditis virus,Theiler's virus, and Mengo virus. MDA5 is important in antiviralactivation against Sendai virus and works cooperatively with RIG-I torespond to West Nile virus, rabies virus, Dengue virus, and rotavirus.Table 2 contains a list of known viral targets of RIG-I and MDA5. Insome embodiments, the combination of levocetirizine and montelukast isused in methods of downregulated MDA-5 activation. In some embodiments,the combination of levocetirizine and montelukast is used in methods oftreating viruses and/or inflammation-related disease by downregulatingactivation of inflammatory responses through the MDA-5 pathway. In someembodiments, the above methods are accomplished using a sustainedrelease formulation. In some embodiments, the sustained releaseformulation targets the NF-kB pathway.

Laboratory of genetics and physiology 2 (LGP2) is another RLR. The LGP2gene lacks the region encoding CARD in RIG-I and MDA5. Since this regionis responsible for association with IPS-1 and therefore furthersignaling events, LGP2 is thought to be a negative regulator of RLRsignaling via interaction between the RD of LGP2 and that of RIG-I. LGP2is assumed to be a modulator of the innate immune response to a viralinfection and not a sensor of PAMPs in that LGP2 does not initiateantiviral gene expression. LGP2 may mediate the modulator role byinhibiting RIG-I signaling via competitive interaction with viral dsRNAspecies in one scenario, while in another, enhancing the ability of MDA5to sense long dsRNA structures by complexing with MDA5. In someembodiments, the combination of levocetirizine and montelukast is usedin methods to treat viruses and/or inflammation-related disease thatelicit inflammation by upregulating the LGP2 pathway. In someembodiments, the combination of levocetirizine and montelukast is usedin methods to treat viruses and/or inflammation-related disease byinterfering with the LGP2 pathway.

Interferon promoter stimulator 1 (IPS-1) is located at the cytosolicface of the outer mitochondrial membrane, and this mitochondrialassociation is initiates further signaling events. Both RIG-I and MDA5interact with the adaptor IPS-1 through CARD repeats. IPS-1-deficientmice are impaired in the production of proinflammatory cytokines andtype I IFN in response to all RNA viruses recognized by RIG-I and MDA5,indicating a key role of IPS-1 in downstream signaling from RIG-I andMDA5. While IPS-1 itself is probably not directly involved in thesignaling process it likely serves plays a role in orchestrating theactivation of IRF3 and NF-kB. In some embodiments, the combination oflevocetirizine and montelukast is used in methods of downregulated IPSmediated activation of IRF3 and NF-kB pathways. In some embodiments, thecombination of levocetirizine and montelukast is used in methods oftreating viruses and/or inflammation-related disease by downregulatingactivation of inflammatory responses through IPS mediated activation ofIRF3 and NF-kB pathways.

Another stimulator of IFN genes, called STING (also called MITA) andfound in the mitochondrial membrane, interacts with RIG-I and IPS-1 inthe mitochondrial membrane—potentially initiating communication betweenorganelles in viral sensing. Given that some viruses replicate in themembranes of organelles, the STING stimulator is a target forinterfering with viral-based inflammation and/or replication. In someembodiments, the combination of levocetirizine and montelukast treatsviruses and/or inflammatory related disease by interfering with theSTING stimulator.

IPS-1 coordinates the activation of two pathways which leads to NF-kBnuclear translocation and the activation of inhibitors of NF-kB kinase(IKK) (see FIG. 1). Central in the initiation of both pathways is theTNF receptor-associated death domain (TRADD), which is recruited toIPS-1 and coordinates interactions with downstream molecules. TheIPS-1/TRADD complex recruits TRAF3, which together with TANK andIKK/NEMO initiates the activation of IKKs. Similarly, this complexrecruits receptor interacting protein 1 (RIP1) (in a complex with theFas-associated death domain [FADD]) for the initiation of the NF-KBpathway. In some embodiments, the combination of levocetirizine andmontelukast treats viral infection or disease at least in part byinterfering with these pathways. As shown in FIG. 1, this interferencemay specifically target the NF-kB receptor.

Not to be bound by a particular theory, in some embodiments, thecellular mechanism of action is proposed to be at least in part areduction of the activation of the intracellular protein complex NF-kB(nuclear factor kappa B) which is in turn responsible for the reductionof certain transmembrane proteins (e.g., I-CAM-1). I-CAM-1, atransmembrane protein, is viewed as the portal of entry of some virusesinto the cell (e.g., rhinovirus). Rhinovirus can be found in ˜50% ofcases of acute asthma and is responsible for 30-50% cases of the “commoncold.” A one-log reduction in viral titers has been independentlydetermined to correlate with improved symptoms. In addition,levocetirizine has been shown to decrease eosinophil migration/quantityand decrease inflammatory mediators, IL-4, IL-6, and IL-8. IL-6, asignaling protein, regulates in part: fever, the body's response totrauma, and the acute (immediate) phase of an immune response. It isbelieved that these same effects through modulation the innate/adaptiveimmune system, may reduce viral titers of one or more of the Ebolavirus, the Dengue virus, the West Nile virus, the Yellow fever virus,and the TBE virus. It is also believed that these effects throughmodulation the innate/adaptive immune system may reduce parasite levelsin, for example, Malaria. Parasitic disease is classically associatedwith an eosinophilic response. Regarding montelukast, the cysteinylleukotrienes (e.g., LTC4, LTD4, LDE4, etc.) are products of arachidonicacid metabolism. These leukotrienes are released from various cellsincluding mast cells and eosinophils. They bind to receptors in thehuman airway and on other pro-inflammatory cells including eosinophilsand certain myeloid stem cells. The cysteinyl leukotrienes have beencorrelated with the pathophysiology of asthma and allergic rhinitis. Insome embodiments, the combination of levocetirizine and montelukasttreats viral infection of disease at least in part by interfering withthese pathways, ligands, and/or receptors.

Without being bound by any particular theory, it is believed that as RLR(RIG-I-like receptor) signaling converges on pathways also utilized bythe TLRs, the induced gene expression is also similar, leading tosynthesis and release of type I IFN s and proinflammatory cytokines inorder to launch an antiviral inflammatory response. RLR signaling ismodified by ubiquitination, direct protein interactions, and caspaseactivity in an elaborate network of both positive and negativeregulation. In some embodiments, the combination of levocetirizine andmontelukast treats viral infection or disease at least in part byinteracting with these pathways.

In addition to the signaling pathway described above, RIG-I activationmay trigger inflammasome formation and cysteine-aspartic protease 1(caspase-1) activity, leading to the maturation of proinflammatorycytokines such as interleukin-1β (IL-1β). This IPS-1-independent pathwayis also used by NLRP3. NLRs or NOD-like receptors (nucleotide-bindingoligomerization domain-containing) are cytosolic proteins regulating theinflammatory and apoptotic responses (NLRP3, NLRC2, and NLRC5). Thesereceptors are additionally important in antiviral defense. In someembodiments, the combination of levocetirizine and montelukast treatsviral infection or disease at least in part through interaction with oneor more of these pathways or ligands.

NLRP3, NOD-like receptor family, pyrin domain-containing 3, presumablythrough lysosomal degeneration and membrane disruption ultimatelymediates the formation of fully functional IL-1β and IL-18. The specificstimuli initiating aggregation of the NLRP3 inflammasome are stillunresolved. It shares a common pathway with NF-kB and is likely anindirect sensor of viral invasion. (Table 3, FIG. 1).

TABLE 3 Individual NLRs and the RNA viruses recognized by them ReceptorVirus Ligand NLRP3 Influenza A virus Virus→cell stress? Sendai virusVirus→cell stress? NLRC2 Respiratory syncytial virus ssRNA Influenza Avirus ssRNA Parainfluenza virus ssRNAFIG. 1 also shows the RIG-1 and NLRP3 signaling pathway. In someembodiments, the combination of levocetirizine and montelukast treatsviral infection of disease at least in part through interaction withthese pathways.

In some embodiments, combined levocetirizine and montelukast therapydecreases, in part, upregulation of ICAM-1 and IL-6. ICAM-1, in theestablished pathway to leucocyte extravasation, is a significantbiomarker for hemorrhage. IL-6 is a significant biomarker for fatality.Ebola is a highly virulent pathogen which operates in part through theICAM-1 and IL-6 pathways. The Ebola virus genus includes five differentviruses: Sudan virus (SUDV), Tai Forest virus (TAFV), Reston virus(RESTV), Ebola virus (EBOV), and Bundibugyo virus (BDBV). Ebola has thehighest fatality rate (25-90%) followed by Sudan virus and has thepresent risk of becoming endemic in Africa. In some embodiments, thecombination of levocetirizine and montelukast are effective for treatingone or more of Sudan virus (SUDV), Tai Forest virus (TAFV), Reston virus(RESTV), Ebola virus (EBOV), and Bundibugyo virus (BDBV).

The incubation period of Ebola virus is between 2-21 [World HealthOrganization] days followed by the onset of headache, fever, extremefatigue, and gastrointestinal distress. Initial principal viral targetsare the dendritic cells (DCs), vascular monocytes, and tissuemacrophages. Infection of the monocytes and macrophages leads to amassive release of pro-inflammatory cytokines and chemokines. This“cytokine storm” recruits additional antigen presenting cells to thesite of infection to escalate the process.

Altered chemistries include, but are not limited to, an elevated AST(aspartate aminotransferase—liver enzyme), D-dimer, blood urea nitrogen,and creatinine. Serum calcium and albumin are lower in fatal cases.Elevated signaling proteins include in part, IL-6, IL-8, Il-10, andmacrophage inflammatory protein 1β (MIP-1β). A rise in an acute phasesignaling protein, IL-6, and ICAM-1 (Intracellular adhesion molecule-1),have been correlated with death and hemorrhage, respectively. In someembodiments, the combination of levocetirizine and montelukast treatsthese viral infections at least in part through interaction with thesepathways.

Clinically, bleeding, petechiae (small hemorrhages) and a maculopapularrash frequently occur between 2 and 7 days. Death can follow and isunderscored by massive tissue injury and multi-organ system failurecharacterized by vascular permeability, dissemination intravascularpermeability and hemorrhage. It is commonly held that the abatement ofthe coagulopathy in both Ebola and sepsis improves survival outcomes.The clinical response to existing therapy has been limited by multiplestrategies through which the virus antagonizes the INF-α and INF-βresponse. Terminal stages of Ebola are underscored by a dysregulatedinflammatory response resulting in vascular permeability, disseminationintravascular coagulation and multiorgan system failure. In someembodiments, the combination of levocetirizine and montelukastalleviates or decreases one or more of bleeding, petechiae (smallhemorrhages), a maculopapular rash, massive tissue injury, multi-organsystem failure characterized by vascular permeability, and deathassociated with Ebola infection.

The Ebola virus as a highly virulent organism has evolved to sustainitself through different pathways. First, two structural proteins, viralprotein 24 (VP24) and viral protein 35 (VP3 5) act in concert todesensitize hosts cells to the effects of IFN-α/β and IFN-γ. Second, theEBOV glycoprotein (GP) facilitates budding from infected cells andparticipates in epitope masking and steric shielding. The resultingdense concentration of glycans creates a difficult environment for thebinding of neutralizing antibodies. The glycan barrier contributes tothe pathogenesis. In some embodiments, the combination of levocetirizineand montelukast treats viral infection at least in part throughinteraction with one or more of these pathways or ligands.

In general RIG-1 is activated by viral RNA to induce a type I IFNresponses to control viral replication. A cellular dsRNA binding proteincalled PACT can also activate RIG-1. Recent science appears to supportthe concept that a mutual antagonism between the Ebola virus VP35protein and RIG-1 activator PACT determines the infection outcome. Thatbeing said, although PACT interacts with the C terminus of RIG-1, thestructural and biochemical basis by which it modulates RIG-1 activationremains incompletely understood.

Ebola as a highly pathogenic organism will more likely than not requiresustained tissue levels to decrease morbidity and mortality (25-90%).Initial flu-like symptoms rapidly progress to severe nausea, diarrhea,shortness of breath, hypotension, bleeding and coma. The current focusof therapy for the Ebola virus is supportive. Traditional measures,assuming such basics are available in medically underserved regions,include intravenous fluid for hydration and maintenance of electrolytebalance, insulin for regulation of glucose, supplemental oxygen whennecessary to provide adequate tissue saturation, analgesics for pain,headache, and myalgia, and prophylactic antibiotics to treat secondaryopportunistic bacterial infections.

The use of platelet transfusions and fresh frozen plasma are thestandard of care for the treatment of DIC (disseminated intravascularcoagulation). Heparin may be of value in patients with low-grade DIC;however, there are no controlled clinical trials. Therapeuticintervention focusing on coagulopathy in nonhuman models of EBOV(Recombinant human activated protein C, Recombinant inhibitor of factorVIIa/tissue factor) have only moderately increased survival. Recentlythe use of statins have been suggested to decrease inflammation andpotentially improve survival; however, IV forms of these medicationshave not been developed.

West Nile virus is an infectious virus transmitted by mosquitos. Likefor Ebola, there are currently no vaccines for West Nile Virus. Symptomsof West Nile infection (when present) typically occur between 2 and 15days after infection and may include one or more of the following:fever, headache, fatigue, muscle pain or aches (myalgia), malaise,nausea, anorexia, vomiting, and rash. In some patients, neurologicaldiseases can occur. Those more susceptible to major symptoms of WestNile virus are the elderly, the very young, or those withimmunosuppression (e.g., medically induced, such as those takingimmunosuppressive drugs, or medically compromised due to a pre-existingmedical condition such as HIV infection). Neurological diseasesassociated with West Nile virus encephalitis, which causes inflammationof the brain, West Nile meningitis, which causes inflammation of themeninges, which are the protective membranes that cover the brain andspinal cord, West Nile meningoencephalitis, which causes inflammation ofthe brain and also the meninges surrounding it, and West Nilepoliomyelitis—spinal cord inflammation, which results in a syndromesimilar to polio, which may cause acute flaccid paralysis.

Like Ebola and West Nile, there are also currently no vaccines for theDengue virus. In Dengue fever (caused by the Dengue virus) symptomstypically occur from about 3 to 14 days after exposure to the virus.Symptoms (where present) can include fever, headache (typically locatedbehind the eyes), muscle and joint pains, rash, nausea, vomiting,bleeding from the mucous membranes of the mouth and nose, leakage ofplasma from the blood vessels (resulting in fluid build-up in theabdomen, loss of circulation and organ dysfunction), dengue shocksyndrome, and hemorrhagic fever.

Yellow Fever is another potentially fatal infectious virus. UnlikeEbola, West Nile, and Dengue virus, a vaccine to Yellow fever exists.Yellow Fever symptoms typically occur approximately 3 to 6 days afterexposure to the yellow fever virus. Most cases only cause a mildinfection with fever, headache, chills, back pain, fatigue, loss ofappetite, muscle pain, nausea, and vomiting. In about 15% of cases,however, people enter a toxic phase of the disease with recurring fever,accompanied by jaundice due to liver damage, abdominal pain, andbleeding in the mouth, the eyes, and the gastrointestinal tract (whichcauses vomit to contain blood). This toxic phase is fatal in about 20%of cases, making the overall fatality rate of the disease about 3%. Insevere epidemics mortality may exceed 50%

Tick-Borne Encephalitis (TBE) is caused by the TBE virus which has threesubtypes: (a) European or Western TBC, (b) Siberian TBE, and (c) FarEastern TBE. TBE can infect the brain (encephalitis), the meninges(meningitis) or both (meningoencephalitis) resulting in a 1% to 2%mortality rate; generally about 5 to 7 days after the onset ofneurologic symptoms.

Each of the Ebola virus, the Dengue virus, the West Nile virus, theYellow fever virus, and the TBE virus, have common inflammatory pathwaysshown above. Clinically effective therapy for a high virulent organism(such as one or more of the Ebola virus, the Dengue virus, the West Nilevirus, the Yellow fever virus, and the TBE virus) requires amultifaceted approach to more than one target within the inflammatorycascade. Using the steroid pathway (FIG. 2) as an accepted andtime-proven clinical model, levocetirizine acts not only at theH1-receptor but also at the level of NF-kB (see FIG. 1). Simultaneouslymontelukast functions at the LTD4 receptor to synergistically decreaseinflammation. In some embodiments, the combination of levocetirizine andmontelukast treats one or more of these viruses by acting on multiplepathways. In some embodiments, the combination of levocetirizine andmontelukast provides a synergistic effect by disrupting differentinflammatory pathways simultaneously. In some embodiments, thecombination of levocetirizine and montelukast is used in methods oftreating any of the viruses listed in any one of Tables 1-3. In someembodiments, the combination of levocetirizine and montelukast is usedin methods of treating any of the viruses listed in any one of Tables1-3 through the synergistic activities of levocetirizine through one ofthe above named pathways and through montelukast's activity through analternative pathway.

Malaria is a mosquito-borne parasite. Signs and symptoms of malariatypically begin 8-25 days following infection; however, symptoms mayoccur later in those who have taken antimalarial medications asprevention. Initial manifestations of the disease—common to all malariaspecies—are similar to flu-like symptoms, and can include headache,fever, shivering, joint pain, vomiting, hemolytic anemia, jaundice,hemoglobin in the urine, retinal damage, and convulsions. The classicsymptom of malaria is paroxysm—a cyclical occurrence of sudden coldnessfollowed by shivering and then fever and sweating, occurring every twodays (tertian fever) in P. vivax and P. ovale infections, and everythree days (quartan fever) for P. malariae. P. falciparum infection cancause recurrent fever every 36-48 hours, or a less pronounced and almostcontinuous fever. Severe malaria is usually caused by P. falciparum(often referred to as falciparum malaria). Symptoms of falciparummalaria arise 9-30 days after infection. Individuals with cerebralmalaria frequently exhibit neurological symptoms, including abnormalposturing, nystagmus, conjugate gaze palsy (failure of the eyes to turntogether in the same direction), opisthotonus, seizures, or coma.

Malaria and other parasitic infections also operate though some of theinflammatory pathways shown above. In some embodiments, the combinationof levocetirizine and montelukast treats one or more parasites by actingon multiple inflammation pathways. In some embodiments, the combinationof levocetirizine and montelukast provides a synergistic effect bydisrupting different inflammatory pathways simultaneously to treatMalaria.

Some embodiments provide the combination of levocetirizine andmontelukast as a medicament for the treatment of viruses and diseasesthat activate innate immune responses or that are exacerbated and/orcaused by immune responses (e.g., the adaptive immune response). In someembodiments, the combination of levocetirizine and montelukast treatsviruses and/or diseases that activate innate immune responses at leastin part via Toll-Like Receptors (TLRs). In some embodiments, thecombination of levocetirizine and montelukast reduces the activation ofone or more elements of the NF-kB family of transcription factors(NF-kB: nuclear factor kappa B) resulting in a therapeutic effect. Insome embodiments, the combination of levocetirizine and montelukastreduces the activation of the NF-kB/toll-like receptors and/or otherintracellular or extracellular protein complexes (e.g., exosomes,histones). In some embodiments, the combination of levocetirizine andmontelukast treats viruses or other diseases that are activated at leastin part through NF-kB. Without being bound to a particular theory,delivery of levocetirizine and montelukast (e.g., sustained,intermittent, or otherwise) will stabilize NF-kB through theoverexpression of the H1-receptor in a dose-dependent manner.

As discussed above, innate immune activation also plays a role inneurodegenerative disease. In neurodegenerative diseases, microgliacells are exposed to activated by pathogens through the triggering ofPRRs, including TLR2, TLR4, and TLR6. In addition to these receptors,some TLR ligands also engage co-receptors such as CD36 (also known asplatelet glycoprotein 4), CD14 and CD47. The activation of TLRs andtheir co-receptors by danger-associated molecular patterns (DAMPs) andPAMPs initiates an immune response. As there is a strong overlap betweenthe signaling pathways that are induced by PAMPs and DAMPs, microgliamay not be able to discriminate between invading pathogens and misfoldedor aberrant endogenous molecular patterns. Various self molecules thatare present in degenerating brains can activate immune receptors—forexample, aggregated amyloid-β and α-synuclein, mutant huntingtin (HTT),mutant superoxide dismutase 1 (SOD1), the SlOOA9-SlOOA8 complex (alsoknown as MRP14-MRP8) and chromogranin A. In some embodiments, thecombination of levocetirizine and montelukast treat neurodegenerativedisease by targeting one or more of these receptors or by blocking oneor more of these ligands from inducing inflammatory activity.

A common feature of neurodegenerative diseases is the excessiveproduction and release of pro-inflammatory cytokines of theinterleukin-1β (IL-1β) family, including IL-1β and IL-18. Inflammasomesconsist of a sensor molecule from the NOD-like receptor (NLR) family orthe pyrin and HIN domain-containing protein (PYHIN) family, the adaptorprotein ASC and caspase 1. The NOD-, LRR- and pyrin domain-containing 3(NLRP3) inflammasome is of particular importance in the development ofacute and chronic inflammatory responses, as it can sense a wide rangeof aggregated molecules. There are other inflammasomes—such as absent inmelanoma 2 (AIM2), NLRP1 and NLRP2—that might have a pathological rolein the brain.

Activated microglia are characterized by the retraction of theirprocesses, which is a phenotypic change that may correlate with animpaired ability to remodel synapses. This effect, along with thesuppressive effects of cytokines and NO, may contribute to impairedsynaptic plasticity in neurodegenerative disease. Furthermore,neuroinflammation restricts the supply of neurotrophic factors to glialcells and likely affects physiological processes that are important forintraneuronal protein handling. Microglial cell-driven neuroinflammationmay not only affect neurons but may also cause detrimental feedbackeffects on microglia in the diseased tissue. For example, sustainedexposure to pro-inflammatory mediators restricts microglial phagocytosisof misfolded and aggregated proteins.

Without being bound to any particular mechanism, pathogens, includingβ-amyloid plaques, are thought to trigger the formation of TLR-2-TLR-6in microglial cells. TLR-2-TLR-6 augments NF-kB signaling which leads tothe assembly of inflammasomes. Inflammasomes then produce cytokines andpro-inflammatory factors including one or more of IL-1β, TNF, IL12p40,IL-12, and IL-23. In some embodiments, the combination of levocetirizineand montelukast disrupt this inflammatory cascade by interfering withthe activation of NF-kB. In some embodiments, the combination oflevocetirizine and montelukast disrupt this inflammatory cascade byinterfering with the release of one or more of IL-1β, TNF, IL12p40,IL-12, and IL-23. In some embodiments, the combination of levocetirizineand montelukast prevent inflammation associated with one or more ofAlzheimer's disease, dementia, dementia with Lewy bodies, Parkinson's,Amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington'sdisease. In some embodiments, the combination of levocetirizine andmontelukast decrease cytokine levels that contribute to the pathology ofone or more of Alzheimer's disease, dementia, dementia with Lewy bodies,Parkinson's, Amyotrophic lateral sclerosis, frontotemporal dementia, andHuntington's disease. In some embodiments, the combination oflevocetirizine and montelukast block inflammation caused by microglialcell activation.

Levocetirizine offers a short time to peak plasma level, 0.9 hr., ashort time to steady state level, 40 hours, a low volume ofdistribution, 0.4 L/kg, and an enhanced receptor affinity of 5× overfirst generation mepyramine in an acidic pH (many acute inflammatorydisease states are associated with acidosis, a low physiologic pH).Levocetirizine has a 24 hour receptor occupancy of ˜75%, the highest ofthe commercially available antihistamines. Receptor occupancy of thesecond generation antihistamines appears to correlate with thepharmacodynamic activity in skin wheal and flare studies and withefficacy in allergen challenge chamber studies. Levocetirizine has beenobjectively established a potent antihistamines through histamineinduced wheal and flare data. For example, levocetirizine at 5 mg perday is more effective than fexofenadine at its commonly prescribed doseof 180 mg per day in the United States. In Europe the adult dose is 120mg per day. Levocetirizine has a lower volume of distribution, greaterhistamine receptor affinity in an inflamed state (low pH), and greaterreceptor occupancy at 24 hours at physiologic doses than fexofenadine.The corresponding values are shown in Table 4.

TABLE 4 COMPARISON BETWEEN FEXOFENADINE AND LEVOCETIRIZINE FexofenadineLevocetirizine Vd -L/kg 5.6 L/kg 0.4 L/kg Receptor affinity in increased2x increased 5x an acidic ph Histamine receptor ~25% ~75% occupancy at24 hours Steady-state level 3 days 40 hours

Leukotriene D₄ is the most potent of the cysteinyl leukotrienes incontracting airway smooth muscle. Leukotriene receptors, such as CysLT₁,are found throughout the cells of the respiratory tree (including airwaysmooth muscle cells and airway macrophages) as well as on otherpro-inflammatory cells in the body, particularly eosinophils and certainmyeloid stem cells. Leukotrienes also function to promote therecruitment of eosinophils, dendritic cells and T cells. Eosinophilinfiltration is considered by some authorities as a hallmark ofinflammation.

Montelukast is FDA approved in the US for the treatment of perennialallergic rhinitis, asthma, seasonal allergic rhinitis, and exercisedinduced bronchospasm. Montelukast has been shown to be ineffective inimproving asthma control or cold symptom scores caused by experimentalrhinovirus infection. Unlike levocetirizine, no decrease in viralshedding was observed in rhinovirus-infected individuals treated withmontelukast and there was no significant difference in reported coldsymptom scores compared to placebo-treated individuals. Analysis ofsecondary outcomes suggests that montelukast may protect againstreductions in lung function and increases in sputum eosinophils causedby common cold infections. During the recovery phase the percentage ofsputum eosinophils was elevated in the placebo group, while themontelukast group remained at baseline levels. Further, peak expiratoryflow was not decreased in the montelukast-treated patients. Montelukasttreatment has no effect on the respiratory symptoms of patients withacute respiratory syncitial virus bronchiolitis. However, some studiesindicate that treatment with montelukast reduced the number of days withworsened asthma symptoms and unscheduled doctor's visits in childrenwith mild allergic asthma and resulted in a modest reduction of symptomsin children with recurrent wheezing when given at the first sign ofupper respiratory tract illness.

Montelukast reaches a steady state level, like the second generationantihistamine, levocetirizine, in less than two days. Unlike othercurrently available leukotriene modulators, zileuton and zafirlukast,routine monitoring of liver function tests is not required. There are nodrug interactions with warfarin, theophylline, digoxin, terfenadine,oral contraceptives, or prednisone.

The two molecules are safe, i.e., FDA approved in the United States forallergic disorders down to age six months. They can be given instead ofor in conjunction with existing therapeutic protocols for the treatmentof, including but not limited to, the Ebola virus, the Dengue virus, theWest Nile virus, the Yellow fever virus, and the TBE virus.Levocetirizine and montelukast can also be given instead of or inconjunction with existing therapeutic protocols for inflammation relatedto, including but not limited to, the Ebola virus, the Dengue virus, theWest Nile virus, the Yellow fever virus, and the TBE virus.

Both medications are pregnancy category B (Table 5).

TABLE 5 PREGNANCY CATEGORY DEFINITIONS Category Definition Explanation AGenerally Controlled studies in pregnant women acceptable show noevidence of fetal risk. B May be Either animal studies show noacceptable risk but human studies not available or animal showed minorrisks and human studies were done and showed no risk. C Use with cautionAnimal studies show risk and if benefits human studies not available orneither outweigh risks animal nor human studies were done. D Use inPositive evidence of life-threatening human fetal risk. emergencies whenno safer drug is available X Do not use Risks involved outweighpotential in pregnancy benefits. Safer alternatives exist.

Existing treatment of inflammation focuses on the underlying conditionand nature of the presentation. Commonly employed are a myriad of agentssuch as: diphenhydramine (Benadryl®), oxygen, epinephrine, steroids,beta-agonists, non-steroidal anti-inflammatory agents (NSAIDS),antipyretics, antibiotics, antifungals, and antivirals. Paradoxically,the commonly employed NSAIDS actually increase the production ofleukotrienes. Antipyretics as a class have been shown in a meta-analysisto increase the mortality rate in influenza animal models.

Steroids, which are widely used to treat inflammation, have significantshort and long-term side-effects (Table 6). With regard to treatinginflammation associated with rhinosinusitis, nasal steroids have theirlimitations, particularly in the elderly and those patients on aspirin,clopidogrel or warfarin prescribed to reduce the risk of stroke andheart attack. Even in patients who do not take these traditional “bloodthinners,” the risk of spontaneous epistaxis from nasal steroid spraysis between 4-22%. The risk of epistaxis is medication dependent.Epistaxis is a significant consideration in many patients 55 or older.

TABLE 6 STEROID SIDE EFFECTS Short term Long term Increased propensityfor opportunistic Glaucoma infection Cataracts Increased blood pressureHigh-blood pressure Mood changes Heart disease Increased blood sugarDiabetes mellitus Increased intraocular pressure Obesity Water retentionAcid reflux/GERD Weight gain Osteoporosis Increased risk for congestiveheart failure Myopathy Flushing Increased propensity for Increasedappetite opportunistic infection Insomnia Cushing syndrome

The typical daily dosage for levocetirizine is 5 mg for adults, andlevocetirizine exhibits the following advantageous properties: i) Shorttime to reach peak plasma levels—0.9 hr; ii) Short time to steady statelevel—40 hrs; iii) Low volume of distribution (goes directly to thetarget receptor); iv) High receptor occupancy at 24 hours 75%; v)Increased receptor affinity in inflamed tissue (acidic pH; up to 5× thatof first generation molecules); vi) Pregnancy category B; vii) FDAapproved down to six months for other disease states, i.e., perennialallergic rhinitis and chronic idiopathic urticaria; viii)Anti-inflammatory properties; and ix) immunologically modulatedanti-viral properties. Studies in humans have shown that doses oflevocetirizine up to 30 mg/day can be safely administered.

Montelukast, a leukotriene receptor antagonist, acts concurrently toprotect the respiratory tree as well as block mediators in theinflammatory cascade. The typical daily dosage of montelukast is 10 mgfor adults, and montelukast exhibits the following advantageousproperties: i) montelukast is a selective receptor antagonist,inhibiting the physiologic action of LTD₄ at the CysLT₁ receptor; ii)montelukast binds with high affinity and selectivity to the CysLT₁receptor without producing any agonist activity; iii) montelukast israpidly absorbed; iv) montelukast reaches a peak plasma concentration in3-4 hours; v) the oral bioavailability and C_(max) of montelukast arenot affected by a standard meal; vi) montelukast has a linearpharmacokinetics to 50 mg; vii) doses as low as 5 mg in adults causesubstantial blockage of LTD₄-induced bronchoconstriction; viii) in aplacebo controlled crossover study, montelukast inhibited early-phasebronchoconstriction due to antigen challenge by 75%; ix) montelukast isFDA approved down to six months of age; and x) montelukast has no druginteractions with warfarin, theophylline, digoxin, terfenadine, oralcontraceptives, or prednisone. Montelukast has been administered atdoses up to 200 mg/day to adult patients for 22 weeks and in short-termstudies, and up to 900 mg/day to patients for approximately one weekwithout clinically relevant side effects.

Accordingly, both levocetirizine and montelukast are pregnancy categoryB in the United States and are FDA approved in the United States down tosix months of age for other disease processes. Moreover, both drugs haveonly once daily dosing, and no routine monitoring of blood work isnecessary for most clinical situations. Further, both drugs exhibitminimal clinically relevant interactions with other medications. Asdescribed herein, both levocetirizine and montelukast [administeredorally] reach steady state levels within two days to rapidly produce asynergistic and complementary anti-inflammatory effect.

Here, we describe the unexpected synergistic effects of combininglevocetirizine and montelukast. Not wishing to be bound by a particulartheory, a detailed examination of the pharmacokinetics of levocetirizineat the cell level illuminates the unique inflammatory properties thatextend beyond the IgE mediated release of histamine including thosepathways disclosed elsewhere herein. Levocetirizine exhibits a lowvolume of distribution (0.4 L/kg), prolonged dissolution time from theH1 receptor in an acidic pH, enhanced receptor affinity as a pure isomerof cetirizine, and the highest receptor occupancy at 24 hours of anycurrently available antihistamine. Such parameters impart aninflammatory effect by down regulating various ligands and cytokinesincluding but not limited to IL-4, IL-6, IL-8 as well as cellularadhesion molecules and ligands as discussed elsewhere herein. The laterare a homogeneous group of inducible immunoglobulins, integrins andselectins involved in cell-to-cell adhesion, cellular recruitment,homing and healing. In addition and as described above, levocetirizinehas been shown in vivo to decrease ICAM-1, IL-6, IL-8, TLR3 expressionand NF-kappa B activation resulting in decreased viral titers (e.g.,human rhinovirus titers by log-2). A one log reduction in viral sheddingresults in a significant clinical benefit in virally-infected patients.Many virus serotypes share the same cellular receptor identifying ICAM-1as the portal of entry into the cell. Levocetirizine inhibitsvirus-induced ICAM-1 and cytokine expression and viral replication.Experimentally, montelukast has been shown to decrease levels of solubleserum ICAM-1 (sICAM-1).

An unmet clinical need exists for the treatment of Ebola virus, WestNile infection, Dengue fever, Yellow Fever, and/or TBE. Not wishing tobe bound by a particular theory, the steroid model suggests thatlevocetirizine acts in a non-IgE-mediated capacity at the level of NF-kB(See FIG. 2) and montelukast acts at the CysLT1 receptor to inhibitinflammation. In some embodiments, inflammation is inhibited by blockingthe physiologic actions of LTD4. Both molecules are known to reduce thequantity of eosinophils and neutrophils/migration to site ofinflammation. Montelukast, in addition, also decreases the recruitmentof dendritic cells and T cells and other inflammation-related cells, animportant concept to the overall approach to treating Ebola virus, WestNile infection, Dengue fever, Yellow Fever, TBE, Alzheimer's disease,dementia, dementia with Lewy bodies, Parkinson's, Amyotrophic lateralsclerosis, frontotemporal dementia, and Huntington's disease.

The actions of levocetirizine plus montelukast surpass the individualphysiologic mechanisms of each, well beyond the treatment of allergicrhinitis and asthma. At least in part, it is the immunologicallymodulated anti-viral and anti-inflammatory properties of levocetirizinevis-a-vis NF-kB, IL-6, ICAM-1, RANTES; the inhibition of the actions ofLTD4 by montelukast, underscored by ability of both levocetirizine andmontelukast to inhibit the eosinophil and neutrophil quantity/migration,which impart synergy in the treatment of viruses selected from the groupconsisting of Ebola virus, West Nile infection, Dengue fever, YellowFever, TBE, Alzheimer's disease, dementia, dementia with Lewy bodies,Parkinson's, Amyotrophic lateral sclerosis, frontotemporal dementia, andHuntington's disease. This synergy is reflected by significantlyimproved clinical outcomes in a myriad of acute and chronic inflammatorydisease states including but not limited to Ebola virus, West Nileinfection, Dengue fever, Yellow Fever, and TBE.

Mechanism of Actions—Synergy within the Inflammatory Pathway

Antihistamine, Leukotriene Receptor Antagonist, NF-kB, IL-6, I-CAM-1,IL-4, IL-8, Eosinophils, RANTES, TLR3, AP-1.

Nuclear factor-k B as a family of transcription factors plays a criticalrole in mediating responses to a remarkable diversity of externalstimuli (see elsewhere herein). In some embodiments, administration of atherapeutically effective amount of the combination of levocetirizineand montelukast can be used in a method of treating each of theconditions disclosed above, including one or more of Ebola virus, WestNile infection, Dengue fever, Yellow Fever, and TBE. In someembodiments, administration of a therapeutically effective amount of thecombination of levocetirizine and montelukast can be used in a method oftreating each of the conditions disclosed above and in, for instance,Tables 1-3, including one or more of Influenza (A and B) virus,vesicular stomatitis virus, human immunodeficiency virus, Sendai virus,lactate dehydrogenase-elevating virus, mouse mammary tumor virus, murineleukemia virus, reoviridae, respiratory syncytial virus, coxsackievirus(B3 and B4), poliovirus, Punta toro virus, Measles virus, lymphocyticchoriomeningitis virus, hepatitis C virus, Newcastle disease virus,nipah virus, rabies virus, Lassa virus, Lymphocytic choriomeningitisvirus, Rift Valley fever virus, Japanese encephalitis virus, Rotavirus,Encephalomyocarditis virus, Theiler's virus, Mengovirus, Murinehepatitis virus, Murine norovirus 1, and Parainfluenza virus. Thisfamily of transcriptional factors (NF-kB) is a pivotal element acrossthe spectrum of inflammation, immunity, cell proliferation,differentiation, and survival. NF-kB is expressed in almost all celltypes and tissues. Specific binding sites are present in thepromoters/enhancers of a large number of genes. Table 7 lists theremarkable array of NF-kB target genes.

TABLE 7 NF-kB Target Genes Cytokines/Chemokines and their ModulatorsImmunoreceptors Proteins Involved in Antigen Presentation Cell AdhesionMolecules Acute Phase Proteins Stress Response Genes Cell SurfaceReceptors Regulators of Apoptosis Growth Factors, Ligands and theirModulators Early Response Genes Transcription Factors and RegulatorsViruses Enzymes Courtesy Boston University Biology

One example of the influential nature the NF-kB family of transcriptionfactors is RANTES (regulated on activation, normal T cell expressed andsecreted) In the ‘late’ or adaptive phase of the immune response, RANTESis a chemokine generally expressed three to five days after T-cellactivation. RANTES expression, mediated exclusively through NF-kB,attracts eosinophils, monocytes, mast cells and lymphocytes, activatesbasophils and induces histamine release from these cells.

Select H1 receptor antagonists (e.g., levocetirizine) have theremarkable ability to inhibit nuclear factor kappa-B (NF-kB) andactivator protein-1 (AP-1) activity though H1 receptor—dependent andindependent mechanisms. The induction of AP-1 and NF-kB activity bymizolastine and desloratadine required overexpression of the H1 receptorin a dose-dependent manner to decrease the tumor necrosis factor-aproduction of the chemokine, RANTES. Diphenhydramine, the prototypefirst generation antihistamine, H2 and H3 receptor antagonists wereineffective.

Mizolastine has not been approved in the United States. Although thebioavailability of mizolastine is high and the drug is mainlymetabolized via glucuronidation, systemic dosing of ketoconazole anderythromycin moderately increases the plasma concentration ofmizolastine.

As such, concomitant use is therefore contraindicated. The concomitantuse of other potent inhibitors or substrates of liver oxidation(cytochrome P450/3A4) with mizolastine must be carried out with caution.Approximately 50% of commonly prescribed medications are metabolized viathe cytochrome P450 3A4 or 2D6 pathways in the liver.

Desloratadine, the long-acting tricyclic metabolite of loratadine, isextensively metabolized through the CYP P450 3A4 and 2D6 pathways. Thehalf-life of 27 hours increases to >50 hours in slow metabolizers (7% ofthe Caucasian and 20% of the African-American population). Moreover, ina double-blind, placebo controlled crossover study, levocetirizine was8× more effective in inhibiting wheal and flare responses in the skin.The pharmacokinetics of both mizolastine and desloratadine do notsupport their use in acute and critical care medicine.

Levocetirizine has been shown to inhibit human rhinovirus (HRV)-inducedICAM-1, cytokine expression, and viral replication in airway epithelialcells from both the nose and lung. Overexpression of the H1 receptor inthe laboratory resulted in the inhibition of the HRV-inducedupregulation of ICAM-1, 11-6, TLR3 expression and NF-kB activation.Levocetirizine reduced the levels of HRV-induced increases in ICAM-1regardless of whether the levocetirizine was added before, after, or atthe time of the HRV infection. The results were in agreement withprevious research on the inhibitory effects of levocetirizine ICAM-1up-regulation.

In some embodiments, the methods described herein involve identifying apatient in need of treatment. Once identified, the patient thecombination of levocetirizine and montelukast is administered to thepatient for a period of time. In some embodiments, the administration ofthe combination can be terminated at a time when the combination is nolonger needed.

In some embodiments, the period of administration comprises a periodstarting when the patient first displays symptoms until a time when theviral infection or disease state is controlled or cured (e.g., the acutesymptoms have subsided, viral titers have decreased to a baseline, riskfactors for disease or viral progression have decreased, etc.). In someembodiments, the period of time comprises a period spanning from whenthe patient or doctor suspects the patient has been exposed to a virusto a time when the patient is no longer at risk of developing acuteinfection from that virus. In some embodiments, the combination oflevocetirizine and montelukast is given to alleviate symptoms of achronic disease and the combination is given for the duration of thedisease state (e.g., for the lifespan of the patient). In someembodiments, the combination of levocetirizine and montelukast isadministered preventatively for a period during high exposure risk orduring a period when the disease is likely to display symptoms.

In some embodiments, patients in need of treatment include those who areat risk for being exposed to viral infection (e.g., by traveling toareas where infectious outbreaks are occurring or have occurred in thepast). In some embodiments, patients in need of treatment can includethose who are at a high likelihood of developing diseases states becauseof genetic factors or due to lifestyle variables (e.g., former drugusers, people who are prone to concussion or have suffered multipleconcussions, those who have family members with neurologic diseases,etc.). In some embodiments, for those at risk patient groups, thecombination of levocetirizine and montelukast can be administered afterage 30, 40, 50, 60, 70, 80, 90, or above, throughout the rest of thepatient's life.

In some embodiments, the patients comprise any type of mammal (e.g.,humans, cows, sheep, horses, cats, dogs, goats, rodents, etc.).

In some embodiments, the levocetirizine montelukast combination isadministered in a sequential manner. In some embodiments, levocetirizineis administered first. In some embodiments, montelukast is administeredfirst. In some embodiments, the combination is administered in asubstantially simultaneous manner.

In some embodiments, levels of levocetirizine utilized in the laboratorymodel can be safely achieved in a clinical setting; however, are abovethe standard adult dose of 5 mg daily used for the treatment of allergyand asthma. In some embodiments, the addition of montelukast, also abovethe standard 10 mg adult dose for allergy and asthma results in aremarkable synergistic effect which has been shown in our clinicalsetting to safely decrease the symptoms and duration of the viralinfection.

In some embodiments, the combination is administered to the patient byone or more of the routes consisting of enteral, intravenous (including,but not limited to a long-acting injectable, e.g., an extended releasepreparation), intraperitoneal, inhalation, intramuscular (including, butnot limited to a long-acting injectable, subcutaneous and oral). In someembodiments, the levocetirizine and montelukast are administered by thesame route. In some embodiments, the levocetirizine and montelukast areadministered by different routes. In some embodiments, the combinationis dosed to the patient using an effective amount of a combination oflevocetirizine and montelukast.

In some embodiments, dosing and delivery of the combination oflevocetirizine and montelukast can be performed for periods between fivedays—twelve months to achieve continuous tissue levels of the drugcombination. In some embodiments, dosing and delivery of levocetirizineand montelukast can be performed for periods of at least about 1 day, 5days, 10 days, 20 days, 30 days, 50 days, 100 days, 200 days, 300 days,ranges and values between the aforementioned values and otherwise. Insome embodiments, the rationale is to achieve sustained tissue levels tomodulate NF-kB at multiple targets within the immune system (Constantoverexpression of the H1 Receptor).

In some embodiments, levocetirizine and montelukast are provided inlong-acting delivery formats to treat the viruses. In some embodiments,the levocetirizine and montelukast are provided in once-daily ormultiple-daily doses. In some embodiments, traditional oral deliverysystems: film strips, bilayer tablets, capsules, tablets, nebulizedtherapy, etc. could be utilized if administered on at least a twicedaily regimen, early in the course of the disease, i.e., the firstseventy-two hours. Otherwise, with the onset of nausea and diarrhea, ormanifestation of any of the systemic indicators: (a) shortness ofbreath, (b) hypotension, (c) bleeding, (d) coma, an IV (intravenous), IM(intramuscular) or LAI (long-acting injectable) can be successful inchanging the outcome (e.g., EBOLA).

Depending upon the patient's age, weight, BMI (body mass index) andseverity of the disease on presentation, the dosing (oral, IV, IM) ordose (LAI) can be titrated to effect over the following range:

Levocetirizine: 1.25-30 mg/24 hours

Montelukast: 4 mg-50 mg/24 hours for a duration of at least five days

Computer modelling should allow for precise dosing and delivery whichwill vary depending upon the nature and extent of the clinicalpresentation.

Given the half-lives of the molecules and other pharmacokineticconsiderations, once oral daily dosing, particularly in an acutely illpatients, may not be effective. As such, in some embodiments, in adifficult-to-treat or harsh environment, a long-acting injectable may beemployed. In some embodiments, a formulation (e.g., a long-actinginjectable) comprising 50-100 mg of levocetirizine and 100-200 mg ofmontelukast within a pharmaceutically acceptable medium or as apharmaceutically acceptable medium (e.g., reconstituted lyophilizedpowder) is dosed to maintain a steady state level for seven days. Insome embodiments, the injectable can be configured to deliver the oralequivalent of between 5 mg and 20 mg of levocetirizine and between 10 mgand 40 mg of montelukast to the patient per day (depending on the natureand extent of the disease process; taking into consideration patientweight, age, etc.). In some embodiments, oral dosing can also be usedwhere appropriate dosing between 5 mg and 20 mg of levocetirizine andbetween 10 mg and 40 mg of montelukast/day, respectively. Divided oraldaily dosing may be employed. In some embodiments, the formulationcomprises about 50 mg, about 100 mg, about 150 mg, about 200 mg, about300 mg, about 400 mg, about 500 mg, or more of levocetirizine. In someembodiments, the formulation comprises about 50 mg, about 100 mg, about150 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, or moreof montelukast.

In some embodiments, long-acting comprises injectables that peak in ashort period of time (e.g., within about 1-3 hours, or less than about 1hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, rangesbetween those values or otherwise). In some embodiments, long-actinginjectables are those that maintain a nearly constant plasma or CNSlevel for a sustained period of time (e.g., about 3 days, about 4 days,about 5 days, about 6 days, about 7 days, about 14 days, about 21 days,about 28 days or more, ranges between those values or otherwise). Insome embodiments, a nearly constant blood concentration is one that isabout 25 ng/mL (combined plateau of both drugs), about 50 ng/mL, about150 ng/mL, about 250 ng/mL, about 350 ng/mL, about 450 ng/mL, about 550ng/mL, about 650 ng/mL, or more (plus or minus about 25-50 ng/mL).

In some embodiments, oral BID dosing can be used to saturatelevocetirizine and montelukast receptors in an estimated ratio of 3 mg/6mg (respectively) one in the AM and two HS (e.g., for Dengue, YellowFever, and TBE. Separately, 6 mg/12 mg at night for long-term treatmentof HIV. In some embodiments, for the innate CNS disorders (e.g.,Alzheimer's, Parkinson's disease and ALS) therapy would be long-term,months to years, qd to bid with an optimal daily dosing range of 6-8mg/12-18 mg: levo/monte; titrated to effect from monthly to quarterlypatient visits, neuropsychiatric assessments at six month intervals andQOL questionnaires at each patient visit. In some embodiments, bothmolecules cross the blood-brain barrier at 0.1 mg/kg. In someembodiments, lower (or higher) dosing could be used.

In some embodiments, the treatments described above further comprise theadministration of a steroid.

The technology has evolved to repurpose levocetirizine+montelukast in along-acting injectable. This concept is particularly useful where thepatient (a) is unable to swallow, (b) where there are limited resourcesfor overall care and management, (c) for prophylaxis in a pandemic, and(d) for use as a bioterrorist counteragent.

Predictive modelling software can be utilized to take existinginformation on the API (active pharmaceutical ingredient), excipients,the desired release profile, and end environment (body v CNS) andcalculate a formulation which can then be used to manufacturemicroparticles that encapsulate the API and release it at the desiredrate. Using computer metrics, the laboratory to manufacturingformulation variances can be minimized during the design phase.

Delivery vehicles include but are not limited to injectablemicroparticles, nanoparticles, matrix implants, and device coatings.Release profiles can be designed as constant rate (where doses arereleased at desired profiles for a period of days, weeks, or months),delayed release, or sequential release. In some embodiments, a widevariety of controlled release systems can be formulated. In someembodiments, the delivery vehicle is an selected from the groupconsisting of injectable microparticle, nanoparticles, pellets, rodsdiscs, tablets, thin film coatings, matrix implants, device coatings,and combinations thereof. In some embodiments, the delivery vehicleformulated from one or more of Poly(lactic-co-glycolic acid) (PLGA),Polyanhydrides (PSA, PSA:FAD), Polylactides (PLA), Poly-ortho-esters(POE), or HPMC hydrogels. The release profile can be tailored betweenConstant Rate (days, weeks, months), Delayed Release, and SequentialRelease.

Proactive inhibition of recognition receptors, for example, theRig-I-like receptor (RLR) in the treatment of EBOLA virus (and/or one ormore of West Nile virus, Dengue virus, tick borne-encephalitis, HIV, andYellow Fever virus, or their respective receptors: West Nile virus—atleast RIG-I, TLR3; Dengue virus—at least RIG-I, MDA5, TLR7; TBE virus—atleast TLR3; HIV—at least TLR7, TLR8; Yellow Fever—at least TLR 7) is animportant tenet. Similarly efficacious is the proactive inhibition ofpathogen recognition receptors (PRRs), for example, the toll-likereceptors in the treatment of parasites (e.g., Malaria and itsrespective receptors—at least TLR7, TLR9). This concept is supported bythe observation that preactivation (or treatment prior to exposure in aclinical setting) of RIG-I reduces EBOV titers in cell culture up to˜1000-fold. Clinically, the magnitude of the viremia has been correlatedwith host survival. Patients with fatal outcomes had higher viral loads,i.e., median tissue culture infective doses (TCID₅₀/ml) of ˜10⁵-10⁶contrasted to 10³-10⁴ in survivors. The combination of levocetirizineand montelukast can be designed in multiple formats as a bioterroristcounteragent.

TCID50/ml is the measure of infectious virus titer. This endpointdilution assay quantifies the amount of virus required to kill 50% ofinfected hosts or to produce a cytopathic effect in 50% of inoculatedtissue culture cells.

Levocetirizine and montelukast also can be used for in the treatment ofHIV: (For instance, an HIV patient with significantly improved CD4 cellcounts (objective measurable data) and additionally the absence ofrespiratory tract infections at 2+ years (i.e., the combined therapy isalso prophylactic against the common cold) on long-termlevocetirizine+montelukast therapy with no interval change in HIVretroviral medications).

In addition to the viruses, parasites and diseases above, thecombination of levocetirizine and montelukast can be used it thetreatment of other viruses and diseases as well. Combination therapycould potentially be applied to any NF-kB dysregulated pathway toimprove quality of life or to treat viral infection and disease. In someembodiments, a medicament comprising levocetirizine or the combinationof levocetirizine and montelukast is used in a method of treating acondition that is, at least in part, mediated by the NF-KB pathway.

For example, some embodiments pertain to the treatment one or more ofAlzheimer's disease, dementia, dementia with Lewy bodies, Parkinson's,Amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington'sdisease by administering a medicament comprising levocetirizine, or thecombination of levocetirizine and montelukast to a patient.

Turning to neuroscience, it has been shown that animal subjected totraumatic brain injury can exhibit elevated levels of NK-kB for up toone year. Activation of the NOD, NLRP3 inflammasome by aberrant hostproteins (the latter of which would also exist in an EBOV infection) isa common step in the development of a diverse array of neurodegenerativedisorders. Understanding that M1-like activated microglial cells areresponsible for chronic brain inflammation, structural damage toneurons, and neuronal dysfunction, with a resultant poor neurologicaloutcome, LAI therapy in a TBI animal model would decrease microglialcell activation through NF-kB.

Separately in a mouse model of amyotrophic lateral sclerosis (ALS),classic NF-kB activation was required to induce motor-neuron death. Theextent of microglial cell activation positively correlated with theseverity of the clinical symptoms.

EXAMPLES Example 1 Ebola Virus

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

A cohort of 40 patients between the ages of 15-30 years of age (with noother co-morbid viral or disease processes) infected with Ebola Virus isidentified. Each patient is identified as having an Ebola symptom (e.g.,one or more of headache, fever, fatigue, myalgia, gastrointestinaldistress, and hemorrhage) ideally within the first 48 hours of symptomonset. The experimental group patients (n=20; “EXPT”) receiveslevocetirizine and montelukast. The control group patients (n=20;“CONT”) receive conventional treatments for EBOLA infection.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history, and previous surgery arelogged at the initial visit and the patient's symptom profile tracked ina controlled environment.

If possible, an applicable quality of life questionnaire is filled outby the patient and health care provider.

Onset, duration, and intensity of symptoms are logged in addition to thetime to resolution of symptoms (time zero—first dose of medication(s)).

Depending upon the treatment location (e.g., Africa) the followingstudies and special chemistries may not be available. If available, thefollowing testing is performed.

Screening laboratory studies consisting of a complete blood count,comprehensive metabolic panel, C-reactive protein, T and B celllymphocyte panel, chest x-ray, EKG, HIV testing, viral cultures, viralload, blood cultures and aerobic cultures of the airway are taken thetime of presentation.

Additional specimens are drawn for analysis:

Once to twice daily serum levels of levocetirizine and montelukast forseven days;

Samples for NF-kB, TLR3, ICAM-1, sICAM-1, RIG-I

Samples for chemokines, cytokines, biomarkers of inflammation, andbiomarkers of coagulopathy. These include but are not limited to:Granulocyte macrophage colony stimulating factor (GM-CSF); GROα;Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin 12p70 (IL-12p70);IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptor antagonist(IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducible protein 10(IP-10); Monocyte chemoattractant protein 1 (MCP-1); Macrophage colonystimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40 ligand (sCD40L);Soluble E-selectin (sE-selectin); Soluble Fas ligand (sFasL); Tumornecrosis factor α (TNF-α); Vascular endothelial growth factor A(VEGF-A); D-dimer; Tissue plasminogen activator (TPA); Plasminogenactivator inhibitor-1 (PAI-1); Serum amyloid antigen (SAA); Regulated onactivation, normal T-cell expressed and secreted (RANTES); sVCAM-1;Fibrinogen; Ferritin; Cortisol; Tissue factor (TF); and Thrombomodulin.

Dosing

In some embodiments, in the treatment of life-threatening disease,sustained tissue levels are used to oversaturate the H1 and leukotrienereceptors in order to achieve the desired clinical outcome. The abovemarkers are used to analyze patient response and further define themechanism of the medication. In some embodiments, one or more of theabove cytokines, chemokines, biomarkers of inflammation, and biomarkersfor coagulopathy return to normal/non-infected levels at an acceleratedrate versus CONT groups.

For levocetirizine, peak concentrations are typically 270 ng/ml and 308ng/ml following a single and repeated 5 mg once daily oral dose,respectively.

For montelukast, the pharmacokinetics are nearly linear for oral dosesup to 50 mg with safety studies up to 900 mg/day for one week. Astandard 10 mg oral dose is reflected by a mean AUC 2689 ng/hr/ml (range1521 to 4595) and mean Cmax of 353 ng/ml.

Given the half-lives of the molecules and other pharmacokineticconsiderations, once daily oral dosing, particularly in an acutely illpatient with nausea and vomiting, may not be effective. As such,particularly in a difficult-to-treat or harsh environment, a long-actinginjectable may be employed. For instance, a long acting injectablecomprising 50-100 mg of levocetirizine and 100-200 mg of montelukastwithin a pharmaceutically acceptable medium (e.g., reconstitutedlyophilized powder) is dosed to maintain a steady state level for sevendays. The injectable can be configured to deliver the oral equivalent ofbetween 5 mg and 20 mg of levocetirizine and between 10 mg and 40 mg ofmontelukast to the patient per day (depending on the nature and extentof the disease process; taking into consideration patient weight, age,etc.). Oral dosing can also be used where appropriate to achieve similarblood levels (e.g., daily, bid, tid, or more).

With a mortality rate of up to 90% it would be considered unethical byinternational standards (World Health Organization) to conduct a placeboarm. As such, 10 EXPT patients would receive a long-acting injectablepreparation (computer modeled on a mg/kg basis) to deliver a sustainedplasma level of both levocetirizine and montelukast in the range of 350ng/ml for 7 days (the EXPT1 group). The second group of 10 patientswould receive a higher dose to sustain plasma levels in the range of 500ng/ml for a period of 7 days (The EXPT2 group), while the CONT groupreceives conventional EBOLA abatement treatments. The EXPT1 and EXPT2groups also receive conventional EBOLA supportive measures in additionto the levocetirizine and montelukast combination.

Outcomes

The primary endpoint of the study is the percentage reduction inmortality when compared to age and symptom matched controls at time zeroas determined from the WHO database. The long-acting injectable is foundto decrease in the mortality by up to 25% base on published mortalityrates of 57-90%. A dose-response curve trending favorably to the higherhigh mean serum concentration range of 500 ng/ml. Levels of IL-6(attenuated by levocetirizine) directly correlate with mortality.

Secondary endpoints are: (a) abatement of the hemorrhage and (b) meantime to clinical resolution.

Hemorrhage is considered an independent variable with no statisticallysignificant difference between hemorrhage and death; however, hemorrhagedoes statistically correlate with the concentration of soluble ICAM-1(sICAM-1). Experimentally, montelukast has been shown to decrease thelevels of sICAM-1.

In summary, treatment of EBOLA with a long-acting injectable containinglevocetirizine and montelukast will significantly decrease the morbidityand mortality associated with the disease.

Patients receiving the levocetirizine and montelukast exhibit lesssevere symptoms. Patients report, on a pain intensity scale (0-10),headaches that are 30% and 60% less intense and fatigue that is 40% and70% less intense in the EXPT1 and EXPT2 groups, respectively, whencompared to the CONT group. Also, 30% and 50% fewer patients displaygastrointestinal distress in the EXPT1 and EXPT2 groups, respectively.Fever levels in EXPT1 and EXPT 2 groups are an average of 2 and 3° F.lower in the EXPT1 group and the EXPT2 group, respectively, than theCONT group after 2 days of dosing. In patients making a full recovery,the patients in the EXPT1 and EXPT2 group have normal temperatures onaverage 3 and 4 days faster than those in the CONT group, respectively.

By day 3 of treatment viral titers in EXPT1 and EXPT2 patients are, onaverage, 25% and 35% lower, respectively, than in the CONT group. Inpatients making a full recovery, the patients in the EXPT1 and EXPT2groups are virus free (by measure of viral titers) on average 3 and 4days faster than those in the CONT group.

The death rate for the EXPT1 and EXPT2 groups at day 14 is 25% and 30%lower, respectively, than the CONT group. Of the survivors, those in theEXPT1 and EXPT2 groups have 30% and 40% lower incidences of prolongedsecondary issues resulting from the acute infection, respectively.Incidences of hemorrhage decrease by 15% and 25% in the EXPT1 and EXPT2groups, respectively, compared to the CONT group. Severity of hemorrhagedecreases by 25% and 45% in the EXPT1 and EXPT2 groups, respectively,compared to the CONT group.

Example 2 EBOLA Virus/Levocetirizine and Montelukast as Adjunct Therapyto Existing Treatment/Novel Antiviral

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

A cohort of 40 patients between the ages of 15-30 years of age (with noother co-morbid viral or disease processes) infected with Ebola Virusare identified. Each patient is identified as having onset of Ebolasymptoms (e.g., one or more of by the onset of headache, fever, fatigue,myalgia, gastrointestinal distress, and hemorrhage) ideally within thefirst 48 hours of symptom onset.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m2), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history, and previous surgery arelogged at the initial visit and the patient's symptom profile tracked ina controlled environment.

If possible an applicable quality of life questionnaire is filled out bythe patient and health care provider.

Onset, duration and intensity of symptoms are logged in addition to thetime to resolution of symptoms (time zero—first dose of medication(s)).

Depending upon the treatment location (e.g., Africa) the followingstudies and special chemistries may not be available.

Screening laboratory studies consisting of a complete blood count,comprehensive metabolic panel, C-reactive protein, T and B celllymphocyte panel, chest x-ray, EKG, HIV testing,

viral cultures, viral load, blood cultures and aerobic cultures of theairway are taken the time of presentation.

Additional specimens are drawn for analysis:

Once to twice daily serum levels of levocetirizine and montelukast forseven days;

Samples for NF-kB, TLR3, ICAM-1, sICAM-1, RIG-I;

Samples for chemokines, cytokines, biomarkers of inflammation, andbiomarkers of coagulopathy. These include but are not limited to:Granulocyte macrophage colony stimulating factor (GM-CSF); GROα;Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin 12p70 (IL-12p70);IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptor antagonist(IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducible protein 10(IP-10); Monocyte chemoattractant protein 1 (MCP-1); Macrophage colonystimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40 ligand (sCD40L);Soluble E-selectin (sE-selectin); Soluble Fas ligand (sFasL); Tumornecrosis factor α (TNF-α); Vascular endothelial growth factor A(VEGF-A); D-dimer; Tissue plasminogen activator (TPA); Plasminogenactivator inhibitor-1 (PAI-1); Serum amyloid antigen (SAA); Regulated onactivation, normal T-cell expressed and secreted (RANTES); sVCAM-1;Fibrinogen; Ferritin; Cortisol; Tissue factor (TF); and Thrombomodulin.

Then existing EBOLA medication(s) including any novel antiviral islogged into the patient record. The above markers are used to analyzepatient response and further define the mechanism of the medication. Insome embodiments, one or more of the above cytokines, chemokines,biomarkers of inflammation, and biomarkers for coagulopathy return tonormal/non-infected levels at an accelerated rate versus CONT groups.

Dosing

With a mortality rate of up to 90% it would be considered unethical byinternational standards (World Health Organization) to conduct a placeboarm.

As such standard or novel EBOLA therapy (experimental or approvedantiviral) is administered at the recommended dose (e.g. brincidofovir)

In the first treatment arm, half the patients, i.e., 20, are given thestandard therapy or antiviral (e.g. brincidofovir) without the LAIcontaining levocetirizine and montelukast. In second arm of the studythe standard therapy or antiviral (e.g., brincidofovir) is given inconjunction with the LAI containing levocetirizine and montelukast. Theduration of the medications are predicated upon the nature and extent ofthe disease process upon presentation or the development ofcomplications during treatment, i.e., the LAI (sustaining serum levelsof approximately 350 ng/ml) may be required at seven day intervals fortwo to three sequential doses depending upon the status of the patient.

Side effects of the medication(s) are recorded for each treatment arm.

Anticipated is a more robust time to resolution, decreased morbidity andoverall mortality rate when contrasted with like patients from the WHOdatabase. Additionally anticipated are fewer overall side effects (e.g.,nausea, urticaria, unanticipated changes in serum chemistries or bloodcount, headache, etc.).

In summary, treatment of EBOLA with standard therapy or a novelantiviral (e.g., brincidofovir) in conjunction with a LAI containing thecombination of levocetirizine and montelukast, would enhance theeffectiveness of that therapy in addition to mitigating side effectsfrom the standard therapy or novel antiviral.

Example 3 West Nile Virus

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

A cohort of 40 patients between the ages of 20-30 years of age (with noother co-morbid viral or disease processes) infected with West Nilevirus is identified. Each patient is identified as having West Nileviral infection symptoms (e.g., one or more of the following: fever,headache, fatigue, muscle pain or aches (myalgia), malaise, nausea,anorexia, vomiting, and rash) ideally within the first 48 hours ofsymptom onset. The experimental group patients (n=20; “EXPT”) receiveslevocetirizine and montelukast as well as conventional West Niletherapies. The control group patients (n=20; “CONT”) receiveconventional therapies for treating West Nile alone.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history and previous surgery arelogged at the initial visit and the patient's symptom profile tracked ina controlled environment.

If possible, an applicable quality of life questionnaire is filled outby the patient and health care provider.

Onset, duration, and intensity of symptoms are logged in addition to thetime to resolution of symptoms (time zero—first dose of medication(s)).

Screening laboratory studies consisting of a complete blood count,comprehensive metabolic panel, C-reactive protein, T and B celllymphocyte panel, chest x-ray, EKG, HIV testing, viral cultures, viralload, blood cultures and aerobic cultures of the airway are taken thetime of presentation.

Additional specimens are drawn for analysis:

Once to twice daily serum levels of levocetirizine and montelukast forseven days;

Samples for NF-kB, TLR7, RIG-I, MDA5, ICAM-1, sICAM-1;

Samples for chemokines, cytokines, biomarkers of inflammation, andbiomarkers of coagulopathy. These include but are not limited to:Granulocyte macrophage colony stimulating factor (GM-CSF); GROα;Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin 12p70 (IL-12p70);IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptor antagonist(IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducible protein 10(IP-10); Monocyte chemoattractant protein 1 (MCP-1); Macrophage colonystimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40 ligand (sCD40L);Soluble E-selectin (sE-selectin); Soluble Fas ligand (sFasL); Tumornecrosis factor α (TNF-α); Vascular endothelial growth factor A(VEGF-A); D-dimer; Tissue plasminogen activator (TPA); Plasminogenactivator inhibitor-1 (PAI-1); Serum amyloid antigen (SAA); Regulated onactivation, normal T-cell expressed and secreted (RANTES); sVCAM-1;Fibrinogen; Ferritin; Cortisol; Tissue factor (TF); and Thrombomodulin.

Dosing

In some embodiments, in the treatment of life-threatening disease,sustained tissue levels are used to oversaturate the H1 and leukotrienereceptors in order to achieve the desired clinical outcome. Forlevocetirizine, peak concentrations are typically 270 ng/ml and 308ng/ml following a single and repeated 5 mg once daily oral dose,respectively. In extreme cases this can be doubled, tripled, otherwiseincreased. In mild cases, this amount can be halved, quartered, orotherwise reduced.

For montelukast, the pharmacokinetics are nearly linear for oral dosesup to 50 mg with safety studies up to 900 mg/day for one week. Astandard 10 mg oral dose is reflected by a mean AUC 2689 ng/hr/ml (range1521 to 4595) and mean Cmax of 353 ng/ml.

Given the half-lives of the molecules and other pharmacokineticconsiderations, once oral daily dosing, particularly in an acutely illpatient with nausea and vomiting, may not be effective. As such,particularly in a difficult-to-treat or harsh environment, a long-actinginjectable may be employed. For instance, a long acting injectablecomprising 50-100 mg of levocetirizine and 100-200 mg of montelukastoptionally within a pharmaceutically acceptable medium (e.g.,reconstituted lyophilized powder) is dosed to maintain a steady statelevel for seven days. The injectable can be configured to deliver theoral equivalent of between 5 mg and 20 mg of levocetirizine and between10 mg and 40 mg of montelukast to the patient per day for seven days(depending on the nature and extent of the disease process; taking intoconsideration patient weight, age, etc., e.g., mean serum concentrationrange of 500 ng/ml Oral dosing can also be used where appropriate toachieve similar blood levels.

The primary endpoint of the study is the percentage reduction inmortality when compared to age and symptom matched controls at time zeroas determined from the WHO database. The long-acting injectable or oraldosing is found to decrease in the encephalitis by up to 50% based onpublished mortality rates.

The secondary endpoint is the mean time to clinical resolution.

Patients receiving the levocetirizine and montelukast exhibit lesssevere symptoms. Patients report, on a pain intensity scale (0-10),headaches and muscle pain are 50% less intense and fatigue is 60% lessintense in the EXPT group when compared to the CONT group. Also, 40%fewer patients display vomiting in the EXPT group. Fever levels in EXPTgroup is an average of 3° F. than the CONT group after 2 days of dosing.In patients making a full recovery, the patients in the EXPT group havenormal temperatures on average 3 days faster than those in the CONTgroup.

By day 4 of treatment, viral titers in EXPT patients are, on average,35% lower than in the CONT group. In patients making a full recovery,the patients in the EXPT group are virus free (by measure of the viralload) on average 3 days faster than those in the CONT group.

Those in the EXPT group have 20% lower incidences of prolonged secondaryissues resulting from the acute infection. Incidences of hemorrhagedecrease by 25% in the EXPT group compared to the CONT group.

Example 4 West Nile Virus Case Study I Overview:

West Nile virus is a mosquito borne virus for which there is currentlyno effective treatment. The disease is characterized by the sudden onsetof an acute, nonspecific flu-like illness lasting 3-6 days, with highfever and chills, malaise, headache, backache, arthralgia, myalgia, andretro-orbital pain without overt neurological signs. Other non-specificfeatures include anorexia, nausea, vomiting, diarrhea, cough and sorethroat. A maculopapular rash has been reported in approximately 50% ofcases.

Neurological disease occurs in fewer than 1% of infected individuals,with a typical prodrome of 1-7 days. Acute flaccid paralysis caused bythe infection of the anterior horn of the spinal cord (myelitis)suggests a clinical picture of poliomyelitis; paralysis is frequentlyasymmetric and may or may not be associated with meningoencephalitis.Once paralysis has been established, little long-term improvement hasbeen described in the literature.

The overall case fatality rate for hospitalized patients ranges from4-14%.

West Nile virus receptors: RIG-I, TLR3 Name: JN DOB: Mar. 24, 1976 Ageat presentation: 36 Date of Exam: October 5

HPI: 36 year old male with a history of West Nile meningitis preceded byonset of backache and fatigue on 09/07. The following day he was seen atan Urgent Care in Newport Beach, Calif. and given oseltamivir (Tamiflu®)75 mg po bid ×five days for a presumed case of influenza. By 09/11symptoms had progressed to include insomnia and severe mid-lower backpain radiating down the left side of his leg. On Wednesday, 09/12, hereturned to Urgent Care and was given oxycodone for pain scaled 7-8/10in addition to ibuprofen 800 mg twice a day.

By 09/14 the patient had developed a low grade fever to 100° F. withchills, myalgia, back pain, and fatigue. Over that weekend he couldbarely get out of bed. On 09/15 he went to a different Urgent Care andwas sent to the Emergency Department at Hoag Hospital, Newport Beach,Calif. The physicians discharged him on ciprofloxacin 500 mg, orallytwice a day and oxycodone with a working diagnosis of acute prostatitis.By 10:30 PM that night he had developed nausea, confusion, and a feverto 102° F. The evening of 09/16 he returned to Hoag Hospital in anambulance and admitted for treatment of West Nile meningitis.

Hospital Stay—9/16-9/21

Over the two weeks prior to our visit on 10/05 he was graduallyimproving; however, continued to exhibit marked fatigue, left lowerextremity weakness, and pain in the lower back and left leg scaled 4/10.Flexeril® (cyclobenzaprine) was taken at night as a muscle relaxant.Physical therapy was ongoing in a frequency of twice a week.

Medications: Flexeril® (cyclobenzaprine) 10 mg, prn, multivitamins

Allergies to Medications: none

Additional major medical problems: none

Surgery: none

Habits:

-   -   Cigarettes—none    -   Alcohol—occasional use

Occupational history: Commercial real estate

Pertinent Physical Examination: 10/05

VS: normal

Weight: 188.9#/85.8.5 kg, previously 205#/93 kg

General: polite male exhibiting significant fatigue and weakness for hisstated age, gait unsteady

Otherwise oriented to time, place and person.

Subtle muscle wasting—left leg

Left leg and lower back pain

Ears: tympanic membranes—gray

Nose: left deviated nasal septum, no erythema

Throat: 2+/4+ tonsils, no evidence of acute infection

Neck: without adenopathy

Lungs: clear

Cor: S1, S2 distinct, no murmur

Chart review - Hoag Hospital Admission 09/16-09/21 Salient information:CPK 803 09/15 (Hoag ED) - elevated, normal <300 IU/L, cardiac arrhythmiaCXR - normal 09/17 09/17 Lumbar puncture CSF protein 108 mg/dl normal12-60  elevated CSF glucose 55 mg/dl normal 40-70  elevated CSF WBC 519/cumm elevated 09/20 WBC 3.6 K/uL normal 4-10 low* 10/05 Laboratory DataPacific Diagnostic Laboratories 89 S. Patterson Ave. Santa Barbara, Ca.Ca. 93111 CBC WBC* 3.6 K/uL normal 4-10 *low; consistent with a viralinfection Hgb 14.3 g/dl normal: 13-17  Note: continued suppression ofthe white blood cell count following discharge 09/21 Hct 42.2% WBC fromSep. 20, 2012-10/05 Platelet count 173 K/uL normal: 150-450  CPK 121IU/L normal: <300   CRP <4.0 mg/L normal <10.0 Sed rate 4 mm/hr normal0.0-15.0 Total IgE 28.3 kU/L normal 0-60 West Nile Ab, IgM - positiveWest Nile Ab, IgG - positive Assessment: West Nile meningitis withfatigue, left lower extremity weakness and pain. Treatment:levocetirizine - 5 mg po hs and montelukast - 10 mg orally at night xsix months to stailize the inflammatory process and enhance recovery.Telephone call (10/25): feeling much better and stronger withsignificantly less fatigue and muscle weakness. Back to work. No sideeffects from medication. Advised to continue levocetirizine andmontelukast through the end of March the following year.

Summary

This is a remarkable case of confirmed West Nile meningitis treated postdischarge from the hospital with levocetirizine and montelukast.Physicians at Hoag Memorial Hospital had informed him it would take ayear to fully recover. He clinically recovered in three weeks with noside effects.

West Nile virus has a variable presentation. Dosing for hospitalizedpatients would range from:

Therapeutic Dosing for Acute Disease:

levocetirizine 10-20 mg, divided dose bid, or in an injectable format toachieve sustained serum levels of at least 350 ng/ml plus

montelukast 20-40 mg/day, divided dose bid, or in an injectable formatto achieve sustained dosing of at least 350 ng/ml.

Higher total daily dosing would be required to treat meningitis ormeningoencephalitis

Both medications, if so required, cross the blood brain barrier at adose of 0.1 mg/kg.

Therapeutic Dosing During the Convalescent Phase of the Disease:

The long-term convalescent dose used in the present case waslevocetirizine—5 mg, orally, and montelukast 10 mg, orally once a day.More significant CNS pathology would require higher dosing.

Example 5 Dengue Fever

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

A cohort of 40 patients between the ages of 20-30 years of age (with noother co-morbid viral or disease processes) infected with Dengue Fevervirus is identified. Each patient is identified as having Denguesymptoms (e.g., headache, muscle and joint pains, rash, nausea,vomiting, bleeding from the mucous membranes of the mouth and nose,leakage of plasma from the blood vessels, dengue shock syndrome, andhemorrhagic fever) ideally within the first 48 hours of symptom onset.The experimental group patients (n=20; “EXPT”) receives levocetirizineand montelukast as well as conventional Dengue fever therapies. Thecontrol group patients (n=20; “CONT”) receive conventional therapies fortreating Dengue fever alone.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history, and previous surgery arelogged at the initial visit and the patient's symptom profile tracked ina controlled environment.

If possible, an applicable quality of life questionnaire is filled outby the patient and health care provider.

Onset, duration, and intensity of symptoms are logged in addition to thetime to resolution of symptoms (time zero—first dose of medication(s)).

Screening laboratory studies consisting of a complete blood count,comprehensive metabolic panel, C-reactive protein, T and B celllymphocyte panel, chest x-ray, EKG, HIV testing, viral cultures, viralload, blood cultures and aerobic cultures of the airway are taken thetime of presentation.

Additional specimens are drawn for analysis:

Once to twice daily serum levels of levocetirizine and montelukast forseven days;

Samples for NF-kB, TLR3, ICAM-1, sICAM-1, RIG-I

Samples for chemokines, cytokines, biomarkers of inflammation, andbiomarkers of coagulopathy. These include but are not limited to:Granulocyte macrophage colony stimulating factor (GM-CSF); GROα;Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin 12p70 (IL-12p70);IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptor antagonist(IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducible protein 10(IP-10); Monocyte chemoattractant protein 1 (MCP-1); Macrophage colonystimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40 ligand (sCD40L);Soluble E-selectin (sE-selectin); Soluble Fas ligand (sFasL); Tumornecrosis factor α (TNF-α); Vascular endothelial growth factor A(VEGF-A); D-dimer; Tissue plasminogen activator (TPA); Plasminogenactivator inhibitor-1 (PAI-1); Serum amyloid antigen (SAA); Regulated onactivation, normal T-cell expressed and secreted (RANTES); sVCAM-1;Fibrinogen; Ferritin; Cortisol; Tissue factor (TF); and Thrombomodulin.

Dosing

In some embodiments, in the treatment of life-threatening disease,sustained tissue levels are used to oversaturate the H1 and leukotrienereceptors in order to achieve the desired clinical outcome. Forlevocetirizine, peak concentrations are typically 270 ng/ml and 308ng/ml following a single and repeated 5 mg once daily oral dose,respectively. In extreme cases this can be doubled, tripled, otherwiseincreased. In mild cases, this amount can be halved or otherwisereduced.

For montelukast, the pharmacokinetics are nearly linear for oral dosesup to 50 mg with safety studies up to 900 mg/day for one week. Astandard 10 mg oral dose is reflected by a mean AUC 2689 ng/hr/ml (range1521 to 4595) and mean Cmax of 353 ng/ml.

Given the half-lives of the molecules and other pharmacokineticconsiderations, once daily oral dosing, particularly in an acutely illpatient with nausea and vomiting, may not be effective. As such,particularly in a difficult-to-treat or harsh environment, a long-actinginjectable may be employed. For instance, a long acting injectablecomprising 50-100 mg of levocetirizine and 100-200 mg of montelukastwithin a pharmaceutically acceptable medium (e.g., reconstitutedlyophilized powder) is dosed to maintain a steady state level for sevendays. The injectable can be configured to deliver the oral equivalent ofbetween 5 mg and 20 mg of levocetirizine and between 10 mg and 40 mg ofmontelukast to the patient per day for seven days (depending on thenature and extent of the disease process; taking into considerationpatient weight, age, etc.). Oral dosing can also be used whereappropriate to achieve similar blood levels.

The primary endpoint of the study is the percentage reduction inmortality when compared to age and symptom matched controls at time zeroas determined from the WHO database. The long-acting injectable is foundto decrease in the mortality by up to 50% base on published mortalityrates with mean serum concentration ranges between 350-500 ng/ml. Levelsof IL-6 (attenuated by levocetirizine) directly correlate withmortality.

Secondary endpoints are: (a) abatement of the symptoms and (b) mean timeto clinical resolution.

Patients receiving the levocetirizine and montelukast exhibit lesssevere symptoms. Patients report, on a pain intensity scale (0-10),headaches and muscle pain are 50% less intense and fatigue is 70% lessintense in the EXPT group when compared to the CONT group. Also, 30%fewer patients display vomiting in the EXPT group. Fever levels in EXPTgroup is an average of 3° F. than the CONT group after 2 days of dosing.In patients making a full recovery, the patients in the EXPT group havenormal temperatures on average 5 days faster than those in the CONTgroup.

By day 4 of treatment, viral titers in EXPT patients are, on average,35% lower than in the CONT group. In patients making a full recovery,the patients in the EXPT group are virus free (by measure of viraltiters) on average 5 days faster than those in the CONT group.

Those in the EXPT group have 20% lower incidences of prolonged secondaryissues resulting from the acute infection. Incidences of hemorrhagedecrease by 25% in the EXPT group compared to the CONT group. Severityof hemorrhage decreases by 45% the EXPT group.

Example 6 Yellow Fever

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

A cohort of 30 patients between the ages of 20-35 years of age (with noother co-morbid viral or disease processes) infected with Yellow Fevervirus is identified. Each patient is identified as having one or moresymptoms (e.g., fever, headache, chills, back pain, fatigue, loss ofappetite, muscle pain, nausea, vomiting, hematemesis, epistaxis nasalbleeding, gum bleeding, gastrointestinal bleeding, and icterus) ideallywithin the first 48 hours of symptom onset. The experimental grouppatients (n=15; “EXPT”) receives levocetirizine and montelukast as wellas conventional Yellow fever therapies. The control group patients(n=15; “CONT”) receive conventional therapies for treating Yellow feveralone.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,social history, cigarette and alcohol use, and previous surgery arelogged at the initial visit and the patient's symptom profile tracked ina controlled environment.

If possible, an applicable quality of life questionnaire is filled outby the patient and health care provider.

Onset, duration, and intensity of symptoms are logged in addition to thetime to resolution of symptoms (time zero—first dose of medication(s)).

Screening laboratory studies consisting of a complete blood count,comprehensive metabolic panel, C-reactive protein, T and B celllymphocyte panel, chest x-ray, EKG, HIV testing, viral cultures, viralload, blood cultures and aerobic cultures of the airway are taken thetime of presentation.

Additional specimens are drawn for analysis:

Once to twice daily serum levels of levocetirizine and montelukast forseven days;

Samples for NF-kB, TLR3, ICAM-1, sICAM-1, TLR-7;

Samples for chemokines, cytokines, biomarkers of inflammation, andbiomarkers of coagulopathy. These include but are not limited to:Granulocyte macrophage colony stimulating factor (GM-CSF); GROα;Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin 12p70 (IL-12p70);IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptor antagonist(IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducible protein 10(IP-10); Monocyte chemoattractant protein 1 (MCP-1); Macrophage colonystimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40 ligand (sCD40L);Soluble E-selectin (sE-selectin); Soluble Fas ligand (sFasL); Tumornecrosis factor α (TNF-α); Vascular endothelial growth factor A(VEGF-A); D-dimer; Tissue plasminogen activator (TPA); Plasminogenactivator inhibitor-1 (PAI-1); Serum amyloid antigen (SAA); Regulated onactivation, normal T-cell expressed and secreted (RANTES); sVCAM-1;Fibrinogen; Ferritin; Cortisol; Tissue factor (TF); and Thrombomodulin.

Dosing

In some embodiments, in the treatment of life-threatening disease,sustained tissue levels are used to oversaturate the H1 and leukotrienereceptors in order to achieve the desired clinical outcome. Forlevocetirizine, peak concentrations are typically 270 ng/ml and 308ng/ml following a single and repeated 5 mg once daily oral dose,respectively. In extreme cases this can be doubled, tripled, otherwiseincreased. In mild cases, this amount can be halved, quartered, orotherwise reduced.

For montelukast, the pharmacokinetics are nearly linear for oral dosesup to 50 mg with safety studies up to 900 mg/day for one week. Astandard 10 mg oral dose is reflected by a mean AUC 2689 ng/hr/ml (range1521 to 4595) and mean Cmax of 353 ng/ml.

Given the half-lives of the molecules and other pharmacokineticconsiderations, once oral daily dosing, particularly in an acutely illpatient with nausea and vomiting, may not be effective. As such,particularly in a difficult-to-treat or harsh environment, a long-actinginjectable may be employed.

For instance, a long acting injectable comprising 50-100 mg oflevocetirizine and 100-200 mg of montelukast within a pharmaceuticallyacceptable medium (e.g., reconstituted lyophilized powder) is dosed tomaintain a steady state level for seven days. The injectable can beconfigured to deliver the oral equivalent of between 5 mg and 20 mg oflevocetirizine and between 10 mg and 40 mg of montelukast to the patientper day for seven days (depending on the nature and extent of thedisease process; taking into consideration patient weight, age, etc.).Oral dosing can also be used where appropriate to achieve similar bloodlevels.

The primary endpoint of the study is the percentage reduction inmortality or symptoms when compared to age and symptom matched controlsat time zero as determined from the WHO database. The long-actinginjectable is found to decrease in the mortality by up to 90% base onpublished mortality rates for patients with toxic phase disease with amean serum concentration level between 350-500 ng/ml. Levels of IL-6(attenuated by levocetirizine) directly correlate with mortality.

The secondary endpoint is the mean time to clinical resolution.

Patients receiving the levocetirizine and montelukast exhibit lesssevere symptoms. Patients report, on a pain intensity scale (0-10),headaches, fever, chills and muscle pain are 40% less intense andfatigue is 50% less intense in the EXPT group when compared to the CONTgroup. Also, 50% fewer patients display vomiting in the EXPT group.Fever levels in EXPT group is an average of 2° F. lower than the CONTgroup after 2 days of dosing. In patients making a full recovery, thepatients in the EXPT group have normal temperatures on average 4 daysfaster than those in the CONT group.

By day 4 of treatment, viral titers in EXPT patients are, on average,55% lower than in the CONT group. In patients making a full recovery,the patients in the EXPT group are virus free (by measure of viraltiters) on average 4 days faster than those in the CONT group.

Those in the EXPT group have 50% lower incidences of prolonged secondaryissues resulting from the acute infection.

Example 7 TBE

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

A cohort of 40 patients between the ages of 20-35 years of age (with noother co-morbid viral or disease processes) infected with TBE virus isidentified. Each patient is identified as having two or more symptoms ofencephalitis or meningitis (and, e.g., fever, headache, malaise, nausea,vomiting, myalgis, and fasiculations). The experimental group patients(n=20; “EXPT”) receives levocetirizine and montelukast as well asconventional TBE therapies. The control group patients (n=20; “CONT”)receive conventional therapies for treating TBE alone.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history and previous surgery arelogged at the initial visit and the patient's symptom profile tracked ina controlled environment.

If possible, an applicable quality of life questionnaire is filled outby the patient and health care provider.

Onset, duration, and intensity of symptoms are logged in addition to thetime to resolution of symptoms (time zero—first dose of medication(s)).

Screening laboratory studies consisting of a complete blood count,comprehensive metabolic panel, C-reactive protein, T and B celllymphocyte panel, chest x-ray, EKG, HIV testing, viral cultures, viralload, blood cultures and aerobic cultures of the airway are taken thetime of presentation.

Additional specimens are drawn for analysis:

Once to twice daily serum levels of levocetirizine and montelukast forseven days;

Samples for NF-kB, TLR3;

Samples for chemokines, cytokines, biomarkers of inflammation, andbiomarkers of coagulopathy. These include but are not limited to:Granulocyte macrophage colony stimulating factor (GM-CSF); GROα;Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin 12p70 (IL-12p70);IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptor antagonist(IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducible protein 10(IP-10); Monocyte chemoattractant protein 1 (MCP-1); Macrophage colonystimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40 ligand (sCD40L);Soluble E-selectin (sE-selectin); Soluble Fas ligand (sFasL); Tumornecrosis factor α (TNF-α); Vascular endothelial growth factor A(VEGF-A); D-dimer; Tissue plasminogen activator (TPA); Plasminogenactivator inhibitor-1 (PAI-1); Serum amyloid antigen (SAA); Regulated onactivation, normal T-cell expressed and secreted (RANTES); sVCAM-1;Fibrinogen; Ferritin; Cortisol; Tissue factor (TF); and Thrombomodulin.

Dosing

In some embodiments, in the treatment of life-threatening disease,sustained tissue levels are used to oversaturate the H1 and leukotrienereceptors in order to achieve the desired clinical outcome. Forlevocetirizine, peak concentrations are typically 270 ng/ml and 308ng/ml following a single and repeated 5 mg once daily oral dose,respectively. In extreme cases this can be doubled, tripled, otherwiseincreased. In mild cases, this amount can be halved, quartered, orotherwise reduced.

For montelukast, the pharmacokinetics are nearly linear for oral dosesup to 50 mg with safety studies up to 900 mg/day for one week. Astandard 10 mg oral dose is reflected by a mean AUC 2689 ng/hr/ml (range1521 to 4595) and mean Cmax of 353 ng/ml.

A long acting injectable comprising 50-100 mg of levocetirizine and100-200 mg of montelukast within a pharmaceutically acceptable medium(e.g., reconstituted lyophilized powder) is dosed to maintain a steadystate level for seven days. The injectable can be configured to deliverthe oral equivalent of between 5 mg and 20 mg of levocetirizine andbetween 10 mg and 40 mg of montelukast to the patient per day for sevendays (depending on the nature and extent of the disease process; takinginto consideration patient weight, age, etc.). Oral dosing can also beused where appropriate to achieve similar blood levels.

The primary endpoint of the study is the percentage reduction insequelae of the disease when compared to age and symptom matchedcontrols at time zero as determined from the WHO database. Thelong-acting injectable is found to decrease the sequelae by of up to 50%base on published data for patients presenting with toxic phase disease.Patients receiving the levocetirizine and montelukast exhibit lesssevere symptoms; have an average 30% reduction in meningitis duration,40% reduction in encephalitis duration, and a 50% reduction in theduration of meningoencephalitis in the EXPT group versus those in theCONT group.

By day 4 of treatment, viral titers in EXPT patients are, on average,55% lower than in the CONT group. In patients making a full recovery,the patients in the EXPT group are virus free (by measure of viraltiters) on average 4 days faster than those in the CONT group.

Those in the EXPT group have up to a 50% lower incidence of prolongedsecondary issues resulting from the acute infection (asthenia, headache,memory loss, decreased concentration, anxiety, and emotional lability).

Example 8 Malaria

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

A cohort of 40 patients between the ages of 20-35 years of age (with noother co-morbid viral or disease processes) infected with Malaria isidentified. Each patient is identified as having one or more of symptomsof Malaria (e.g., headache, fever, shivering, joint pain, vomiting,hemolytic anemia, jaundice, hemoglobin in the urine, retinal damage, andconvulsions). The experimental group patients (n=20; “EXPT”) receiveslevocetirizine and montelukast as well as conventional Malariatherapies. The control group patients (n=20; “CONT”) receiveconventional therapies for treating Malaria alone.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history and previous surgery arelogged at the initial visit and the patient's symptom profile tracked ina controlled environment.

If possible, an applicable quality of life questionnaire is filled outby the patient and health care provider.

Onset, duration, and intensity of symptoms are logged in addition to thetime to resolution of symptoms (time zero—first dose of medication(s)).

Screening laboratory studies consisting of a complete blood count,comprehensive metabolic panel, parasite analysis, C-reactive protein, Tand B cell lymphocyte panel, chest x-ray, EKG, HIV testing, viralcultures, viral load, blood cultures and aerobic cultures of the airwayare taken the time of presentation.

Additional specimens are drawn for analysis:

Once to twice daily serum levels of levocetirizine and montelukast forseven days;

Samples for NF-kB, TLR3, TLR7, TLR9;

Samples for chemokines, cytokines, biomarkers of inflammation, andbiomarkers of coagulopathy. These include but are not limited to:Granulocyte macrophage colony stimulating factor (GM-CSF); GROα;Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin 12p70 (IL-12p70);IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptor antagonist(IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducible protein 10(IP-10); Monocyte chemoattractant protein 1 (MCP-1); Macrophage colonystimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40 ligand (sCD40L);Soluble E-selectin (sE-selectin); Soluble Fas ligand (sFasL); Tumornecrosis factor α (TNF-α); Vascular endothelial growth factor A(VEGF-A); D-dimer; Tissue plasminogen activator (TPA); Plasminogenactivator inhibitor-1 (PAI-1); Serum amyloid antigen (SAA); Regulated onactivation, normal T-cell expressed and secreted (RANTES); sVCAM-1;Fibrinogen; Ferritin; Cortisol; Tissue factor (TF); and Thrombomodulin.

Dosing

In some embodiments, in the treatment of life-threatening disease,sustained tissue levels are used to oversaturate the H1 and leukotrienereceptors in order to achieve the desired clinical outcome. Forlevocetirizine, peak concentrations are typically 270 ng/ml and 308ng/ml following a single and repeated 5 mg once daily oral dose,respectively. In extreme cases this can be doubled, tripled, otherwiseincreased. In mild cases, this amount can be halved, quartered, orotherwise reduced.

For montelukast, the pharmacokinetics are nearly linear for oral dosesup to 50 mg with safety studies up to 900 mg/day for one week. Astandard 10 mg oral dose is reflected by a mean AUC 2689 ng/hr/ml (range1521 to 4595) and mean Cmax of 353 ng/ml.

A long acting injectable comprising 50-100 mg of levocetirizine and100-200 mg of montelukast within a pharmaceutically acceptable medium(e.g., reconstituted lyophilized powder) is dosed to maintain a steadystate level for seven days. The injectable can be configured to deliverthe oral equivalent of between 5 mg and 20 mg of levocetirizine andbetween 10 mg and 40 mg of montelukast to the patient per day for sevendays (depending on the nature and extent of the disease process; takinginto consideration patient weight, age, etc.). Oral dosing can also beused where appropriate to achieve similar blood levels.

The primary endpoint of the study is the percentage reduction inmortality or symptoms when compared to age and symptom matched controlsat time zero as determined from the WHO database. Patients receiving thelevocetirizine and montelukast exhibit less severe symptoms.

Patients receiving the levocetirizine and montelukast exhibit lesssevere symptoms. Patients report, on a pain intensity scale (0-10),headaches, fever, chills and muscle pain are 20% less intense andfatigue is 30% less intense in the EXPT group when compared to the CONTgroup. Also, 50% fewer patients display vomiting in the EXPT group.Fever levels in EXPT group is an average of 2° F. than the CONT groupafter 2 days of dosing. In patients making a full recovery, the patientsin the EXPT group have normal temperatures on average 4 days faster thanthose in the CONT group.

Example 8 HIV

HIV is a single-stranded RNA retrovirus that may present as amononucleosis type syndrome with a myriad of nonspecific symptoms. Thisconstellation of symptoms is also known as the acute retroviralsyndrome. The most common findings are fever, lymphadenopathy, sorethroat, rash myalgia/arthralgia and headache. None of the findings arespecific for acute HIV infection but certain features, especiallyprolonged duration of symptoms and the presence of mucocutaneous ulcersare suggestive of the diagnosis.

The presence and increased severity and the duration of symptoms appearto be poor prognostic factors. Following HIV seroconversion, eachadditional symptom present at the time of acute infection is associatedwith an increasing risk of overall mortality.

The differential diagnosis of acute HIV infection includes mononucleosisdue to Epstein-Barr virus, cytomegalic virus (CMV), toxoplasmosis,rubella, syphilis, viral hepatitis, disseminated gonococcal infection,and other infections.

Diagnosis of acute or early HIV infection is established by thedetection of HIV viremia in a setting of a particular HIV serologicaltest pattern. Early HIV infection is characterized by markedly elevatedHIV RNA levels, easily detectable with the HIV RNA (viral load) assayscommonly used for monitoring of HIV disease. In a study of 436 patientswith symptoms consistent with acute HIV infection all the 54 patientsdiagnosed with acute HIV had RNA levels greater than 100,000 copies perml.

Opportunistic infections are usually associated with later stage HIVdisease. Eradication of the latent reservoir of HIV has been a focus ofnovel interventions aimed at curing the infection.

Population-based studies of the natural history of HIV infection havesuggested that the main CD4 cell count is approximately 1000 cells permicroliter prior to seroconversion and decreases to 780 cells permicroliter at 6 months following seroconversion and to 670 cells permicroliter at one year. With depletion of CD4 cells, humoral immunitywanes over time. The acquired immunodeficiency syndrome (AIDS) is theoutcome of chronic HIV infection and consequent depletion of CD4 cells.AIDS is defined as a CD4 cell count less than 200 cells per microliteror in the presence of any AIDS defining condition regardless of the CD4cell count. AIDS defining conditions are opportunistic illnesses thatoccur more frequently or more severely because of immunosuppression.These include many opportunistic infections, but also certainmalignancies as well as conditions without a clear alternative etiologythought to be related to the uncontrolled HIV infection itself such aswasting or encephalopathy.

This case represents a patient with chronic HIV treated withlevocetirizine and montelukast over a period of 3 years. During thatperiod on standard retroviral therapy the CD4 count significantlyincreased. There have been no infections.

HIV receptors: TLR7, TLR8 Name: GT DOB: Oct. 16, 1951 Age at first visit55 Date of initial examination: Jan. 15, 2007

HPI: The patient is a 63-year-old male originally seen in the office in2007 with a diagnosis of chronic sinusitis. The history sinusitis datesback to 2000 at which time he underwent endoscopic sinus surgery at UCLAwithout improvement.

Symptoms included facial pressure, post nasal drainage, eustachian tubedysfunction, and headaches occurring in the frequency of 2 to 3 timesper week, lasting for hours and scaled 5-6/10. Previous allergy testinghad the documented sensitivities to mugwort and peanut. A CT Scan of theSinuses obtained at Santa Barbara cottage Hospital Jan. 5, 2007demonstrated opacification of the right frontal sinusitis and an osteomain the left frontal sinus. Initial medical management included dailyNasonex® (mometasone), a steroid nasal spray, Allegra® (fexofenadine)and an immune workup.

Levocetirizine was initiated in October 2007 followed by the addition ofmontelukast in 2008 Generic levocetirizine utilized in 2012 was switchedto ‘brand’ given the pharmacokinetic and dosing variances encounteredwith the generic product.

Past Medical/Surgical History

HIV infection

Parkinson's disease

congestive cardiomyopathy

degenerative disc disease

hypothyroidism on replacement

pulmonary embolism 09/09

asthmatic bronchitis

chronic sinusitis status post surgery 2000

right shoulder surgery, 2004

left shoulder surgery, 1996

low back pain L5-S1 decompression surgery 2013

Medications:

levocetirizine 5 mg per day

montelukast 10 mg per day

aspirin 81 mg orally per day

Cozaar® (losartan)25 mg per day—ARBs

carvedilol 6.25 mg twice a day

spironolactone 25 mg per day

Duratuss® (dextromethorphan/guaifenesin) 10/200 one daily

testosterone 200 mg IM weekly

Epzicom® (300 mg lamivudine/600 mg abacavir) daily for HIV

Viramune® (nevirapine) 400 mg per day for HIV

Nasacort (triamcinolone) two puff each nostril bid

Astelin (azelastine) 2 puffs each nostril bid, as needed

ropinirole 0.75 mg three times per day

Nandrolone 200 mg IM per week

Cialis 5 mg per day

Atrovent 2 puffs each nostril as needed

carisoprodol 350 mg as needed—muscle relaxant

hydrocodone/acetaminophen (10 mg/325 mg) as needed for pain

Allergies to Medications: ciprofloxacin, Coreg (confusion)

Habits:

-   -   Cigarettes—none    -   Alcohol—none

Occupational history: retired from the film making industry

Review of Systems: Mar. 9, 2015

General: no recent fevers, chills or weight loss.

HEENT: no headache, visual or auditory changes. Chronic sinusitis.

Pulmonary: history of asthmatic bronchitis. No recent cough, sputum,hemostasis, or wheezing

Cardiovascular: congestive cardiomyopathy

Gastrointestinal: no nausea, vomiting, diarrhea, constipation, historyof G.I. bleeding, or peptic ulcer disease.

Genitourinary: no nocturia, dysuria, urgency, frequency, hematuria ordecrease stream.

Musculoskeletal: joint pain—shoulder and back

Skin: no recent lesions

Endocrine thyroid disease. No diabetes.

Neurologic: no TIA, CVA or seizures.

Psychiatric: no anxiety or depression.

Objective Findings:

Vital signs: weight 219 pounds, height 6′1″, BMI 28.89 kg/m2

B/P 140/84, heart rate 79 and regular, respiratory rate 14 andunlabored.

ENT:

Ears: gray tympanic membranes

Nose: open anterior airway, 2×3.5 cm septal perforation, no evidenceinfection

Throat: 2+ tonsils, no erythema.

Neck: supple no JVD. Normal carotid pulses, without 3. No thyromegaly

Laboratory Data:

Salient information:

Apr. 30, 2015

Laboratory Data Pacific Diagnostic Laboratories 89 S. Patterson Ave.Santa Barbara, Ca. Ca. 93111 CBC WBC* 7.0 K/uL normal  4-10 Hgb 15.7g/dl normal: 13-17 Hct 47.9 % Platelet count 294 K/uL normal: 150-450Comprehensive metabolic panel - normal CRP 11.1 mg/L normal <10.0elevated/very

HIV-1 RNA by PCR <20 copies/ml The reportable range for this test is20-10,000,000.

Jul. 21, 2011 CD4 helper count 689 2015 CD4 helper count >1100

Assessment/Summary:

63 year old male with multiple major medical problems as delineated

-   -   Congestive cardiomyopathy    -   HIV    -   Chronic sinusitis

CD4 helper count stabilized/improved on levocetirizine and montelukastover the past three years with no change in retroviral therapy/HIV-1 RNAby PCR—normal.

No significant interval infection. Note, the patient's Parkinson'sdisease also stabilized under the combination dose of montelukast andlevocetirizine provided.

Based on these clinical results using levocetirizine and montelukast,the following results are projected using controlled studies. Patientsusing a combination of levocetirizine and montelukast experience delayedprogression of HIV, decreased HIV symptoms, reduced incidence ofopportunistic infection, and an increased quality of life.

Example 9 Alzheimer's Disease

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

Alzheimer's disease is a progressive and fatal neurodegenerative diseaseaffecting motor neurons in the spinal cord, motor cortex, and brain. Itis characteristically a disease of older age and exceptional to occurbefore the age of 60. The incidence and prevalence increaseexponentially with age. Cardinal symptoms are memory impairment andoften the earliest symptom. Language and visual spatial skills tend tobe affected relatively early, while deficits in executive function andbehavioral symptoms often manifest later in the disease course.

A cohort of 60 patients with Alzheimer's disease between the ages of60-70 years of age is identified by both a neurologist andneuropsychiatrist. A detailed cognitive and general neurologicalexamination is paramount, complete with the use of standardized mentalstatus scales, in particular, the Mini-Mental Status Examination (MMSE),to document the progression of dementia and the Montreal CognitiveAssessment (MoCA) owing to its superior sensitivity in detecting mildcognitive impairment and increased sensitivity to executive and languagedysfunction. A neurophyschological assessment will establish a baselinein order to follow the patient over time.

The differential diagnosis includes dementia with Lewy bodiesparenthesis DLB) which may be the 2^(nd) most common type ofdegenerative dementia after Alzheimer's disease. Clinical features thathelp distinguish dementia with Lewy bodies from Alzheimer's diseaseinclude prominent early appearance of visual hallucinations, along withparkinsonism, cognitive fluctuations, dysautonomia, sleep disorders, andneuroleptic sensitivity.

Routine laboratory tests are generally not useful in the positivediagnosis of Alzheimer's disease; however, some laboratory testing(e.g., complete blood count, comprehensive metabolic panel, thyroidfunction studies, vitamin B12) are indicated to excludeother/contributing secondary causes.

The experimental group patients (n=20; “EXPT1”) receives levocetirizineand montelukast once a day. The experimental group patients (n=20;“EXPT2) receives levocetirizine and montelukast twice a day. The controlgroup patients (n=20; “CONT”) receive a placebo

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history, and previous surgery arelogged at the initial visit and the patient's overall status trackedmonthly over one year.

Additional specimens are drawn for analysis:

Serum levels of levocetirizine and montelukast monthly;

Sample for NF-kB, initially and at the conclusion of the study;

Samples for chemokines, cytokines, and biomarkers of inflammation at thetime of entry into the study and at completion (52 weeks). These includebut are not limited to: Granulocyte macrophage colony stimulating factor(GM-CSF); GROα; Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin12p70 (IL-12p70); IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptorantagonist (IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducibleprotein 10 (IP-10); Monocyte chemoattractant protein 1 (MCP-1);Macrophage colony stimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40ligand (sCD40L); Soluble E-selectin (sE-selectin); Soluble Fas ligand(sFasL); Tumor necrosis factor α (TNF-α); Serum amyloid antigen (SAA);regulated on activation, normal T-cell expressed and secreted (RANTES);Cortisol; CSF for molecular biomarkers of Aβ protein deposition: CSFAβ42, total tau and phosphor-tau initially and at the completion of thestudy.

Imaging: MRI of the brain

Dosing

-   “EXPT1”—levocetirizine 5 mg, orally at night, montelukast 10 mg    orally at night-   “EXPT2”—levocetirizine: 2.5 mg orally in the morning and 5.0 mg    orally at night plus montelukast: 5 mg orally in the morning and 10    mg orally at night-   “CONT”—placebo

Outcome

The clinical course, as measured by the MMSE and Clinical DementiaRating Scale is not necessarily linear, however, a number of studieshave found that patients decline 3 to 3.5 points on the average on theMMS capital E each year, with a minority (<10%) having a more rapidlyprogressive decline of 5 to 6 points on annual MMSE.

Patients receiving the levocetirizine and montelukast (EXPT1 and EXPT2)remain at baseline or deteriorate more slowly the control group (CONT),based on multiple scales of clinical efficacy.

Patient receiving bid dosing of levocetirizine and montelukast (EXPT2)remain at baseline or deteriorate even more slowly than the group dosedonce per day (EXPT1) or (CONT), based on multiple scales of clinicalefficacy. The EXPT1 group declines at 20% the rate of the CONT group andthe EXPT2 group declines at 15% the rate of the CONT group.

Both (EXPT1) and (EXPT2) have a lower dropout rate than the controlgroup, (CONT) (a dropout rate that is 40% and 20% of that of the CONTgroup for EXPT1 and EXPT2, respectively)

In summary, levocetirizine and montelukast significantly decreases therate of clinical deterioration when administered to a group ofAlzheimer's patients over one year.

Example 10 Dementia

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

Dementia (or senility) is a broad category of brain diseases that causea long term and often gradual decrease in the ability to think andremember such that a person's daily functioning is affected. This broadcategory comprises Alzheimer's disease, vascular dementia, Lewy bodydementia, and frontotemporal dementia, among others (e.g., normalpressure hydrocephalus, Parkinson's disease, syphilis, andCreutzfeldt-Jakob disease, etc.). Other common symptoms includeemotional problems, problems with language, and a decrease inmotivation. For the diagnosis to be present it must be a change from aperson's usual mental functioning and a greater decline than one wouldexpect due to aging. The incidence and prevalence increase with age.Cardinal symptoms are memory impairment and often the earliest symptom.Language and visual spatial skills tend to be affected relatively early,while deficits in executive function and behavioral symptoms oftenmanifest later in the disease course.

A cohort of 60 patients with dementia between the ages of 60-70 years ofage is identified by both a neurologist and neuropsychiatrist. Adetailed cognitive and general neurological examination is paramount,complete with the use of standardized mental status scales, inparticular, the Mini-Mental Status Examination (MMSE), to document theprogression of dementia and the Montreal Cognitive Assessment (MoCA)owing to its superior sensitivity in detecting mild cognitive impairmentand increased sensitivity to executive and language dysfunction. Aneurophyschological assessment will establish a baseline in order tofollow the patient over time.

The experimental group patients (n=20; “EXPT1”) receives levocetirizineand montelukast once a day. The experimental group patients (n=20;“EXPT2) receives levocetirizine and montelukast twice a day. The controlgroup patients (n=20; “CONT”) receive a placebo.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history, and previous surgery arelogged at the initial visit and the patient's overall status trackedmonthly over one year.

Additional specimens are drawn for analysis, which include:

Serum levels of levocetirizine and montelukast monthly;

Sample for NF-kB, initially and at the conclusion of the study;

Samples for chemokines, cytokines, and biomarkers of inflammation at thetime of entry into the study and at completion (52 weeks). These includebut are not limited to: Granulocyte macrophage colony stimulating factor(GM-CSF); GROα; Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin12p70 (IL-12p70); IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptorantagonist (IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducibleprotein 10 (IP-10); Monocyte chemoattractant protein 1 (MCP-1);Macrophage colony stimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40ligand (sCD40L); Soluble E-selectin (sE-selectin); Soluble Fas ligand(sFasL); Tumor necrosis factor α (TNF-α); Serum amyloid antigen (SAA);regulated on activation, normal T-cell expressed and secreted (RANTES);Cortisol; CSF for molecular biomarkers of Aβ protein deposition: CSFAβ42, total tau and phosphor-tau initially and at the completion of thestudy.

Imaging: MRI of the brain

Dosing

-   “EXPT1”—levocetirizine 5 mg, orally at night, montelukast 10 mg    orally at night-   “EXPT2”—levocetirizine: 2.5 mg orally in the morning and 5.0 mg    orally at night plus montelukast: 5 mg orally in the morning and 10    mg orally at night-   “CONT”—placebo

Outcome

The clinical course, as measured by the MMSE and Clinical DementiaRating Scale is not necessarily linear, however, a number of studieshave found that patients decline 3 to 3.5 points on the average on theMMS capital E each year, with a minority (<10%) having a more rapidlyprogressive decline of 5 to 6 points on annual MMSE.

Patients receiving the levocetirizine and montelukast (EXPT1 and EXPT2)remain at baseline or deteriorate more slowly the control group (CONT),based on multiple scales of clinical efficacy. Patient receiving biddosing of levocetirizine and montelukast (EXPT2) remain at baseline ordeteriorate even more slowly than the group dosed once per day (EXPT1)or (CONT), based on multiple scales of clinical efficacy. The EXPT1group declines at 20% the rate of the CONT group and the EXPT2 groupdeclines at 15% the rate of the CONT group.

Both (EXPT1) and (EXPT2) have a lower dropout rate than the controlgroup, (CONT) (a dropout rate that is 40% and 20% of that of the CONTgroup for EXPT1 and EXPT2, respectively)

In summary, levocetirizine and montelukast significantly decreases therate of clinical deterioration when administered to a group of dementiapatients over one year.

Example 11 Dementia with Lewy Bodies

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

Dementia with Lewy Bodies (LBD) is a form of dementia closely associatedwith Parkinson's disease. It is characterized anatomically by thepresence of Lewy bodies, clumps of alpha-synuclein and ubiquitin proteinin neurons, detectable in post mortem brain histology. LBD is aprogressive degenerative dementia primarily affecting older adults thatmanifests as cognitive decline, which can lead to hallucinations, aswell as varied attention and alertness when compared to a person'sbaseline function. Persons with LBD display an inability to plan or aloss of analytical or abstract thinking and show markedly fluctuatingcognition. Often wakefulness varies from day to day, and alertness andshort-term memory rise and fall. REM sleep behavior disorder (RBD) is asymptom often first recognized by the patient's caretaker. RBD includesvivid dreaming, with persistent dreams, purposeful or violent movements,and falling out of bed. Persistent or recurring visual hallucinationswith vivid and detailed pictures are often an early diagnostic symptom.LBD symptoms overlap clinically with Alzheimer's disease and Parkinson'sdisease, but are more commonly associated with the latter. Because ofthis overlap, LBD in its early years is often misdiagnosed.

A cohort of 60 patients with LBD between the ages of 60-70 years of ageis identified by both a neurologist and neuropsychiatrist. A detailedcognitive and general neurological examination is paramount, completewith the use of standardized mental status scales, in particular, theMini-Mental Status Examination (MMSE), to document the progression ofLBD and the Montreal Cognitive Assessment (MoCA) owing to its superiorsensitivity in detecting mild cognitive impairment and increasedsensitivity to executive and language dysfunction. A neurophyschologicalassessment will establish a baseline in order to follow the patient overtime.

The experimental group patients (n=20; “EXPT1”) receives levocetirizineand montelukast once a day. The experimental group patients (n=20;“EXPT2) receives levocetirizine and montelukast twice a day. The controlgroup patients (n=20; “CONT”) receive a placebo.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history, and previous surgery arelogged at the initial visit and the patient's overall status trackedmonthly over one year.

Additional specimens are drawn for analysis, which include:

Serum levels of levocetirizine and montelukast monthly;

Sample for NF-kB, initially and at the conclusion of the study;

Samples for chemokines, cytokines, and biomarkers of inflammation at thetime of entry into the study and at completion (52 weeks). These includebut are not limited to: Granulocyte macrophage colony stimulating factor(GM-CSF); GROα; Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin12p70 (IL-12p70); IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptorantagonist (IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducibleprotein 10 (IP-10); Monocyte chemoattractant protein 1 (MCP-1);Macrophage colony stimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40ligand (sCD40L); Soluble E-selectin (sE-selectin); Soluble Fas ligand(sFasL); Tumor necrosis factor α (TNF-α); Serum amyloid antigen (SAA);regulated on activation, normal T-cell expressed and secreted (RANTES);Cortisol; CSF for molecular biomarkers of Aβ protein deposition: CSFAβ42, total tau and phosphor-tau initially and at the completion of thestudy.

Imaging: MRI of the brain

Dosing

-   “EXPT1”—levocetirizine 5 mg, orally at night, montelukast 10 mg    orally at night-   “EXPT2”—levocetirizine: 2.5 mg orally in the morning and 5.0 mg    orally at night plus montelukast: 5 mg orally in the morning and 10    mg orally at night-   “CONT”—placebo

Outcome

The clinical course, as measured by the MMSE and Clinical DementiaRating Scale is not necessarily linear, however, a number of studieshave found that patients decline 3 to 3.5 points on the average on theMMS capital E each year, with a minority (<10%) having a more rapidlyprogressive decline of 5 to 6 points on annual MMSE.

Patients receiving the levocetirizine and montelukast (EXPT1 and EXPT2)remain at baseline or deteriorate more slowly the control group (CONT),based on multiple scales of clinical efficacy. Patient receiving biddosing of levocetirizine and montelukast (EXPT2) remain at baseline ordeteriorate even more slowly than the group dosed once per day (EXPT1)or (CONT), based on multiple scales of clinical efficacy. The EXPT1group declines at 10% the rate of the CONT group and the EXPT2 groupdeclines at 5% the rate of the CONT group.

Both (EXPT1) and (EXPT2) have a lower dropout rate than the controlgroup, (CONT) (a dropout rate that is 40% and 20% of that of the CONTgroup for EXPT1 and EXPT2, respectively)

In summary, levocetirizine and montelukast significantly decreases therate of clinical deterioration when administered to a group of LBDpatients over one year.

Example 12 Parkinson's Disease

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

Parkinson's Disease (also known as idiopathic or primary parkinsonism,hypokinetic rigid syndrome, or paralysis agitans) is a degenerativedisorder of the central nervous system mainly affecting the motorsystem. Parkinson's disease may manifest from the death ofdopamine-generating cells in the substantia nigra, a region of themidbrain. Early in the course of the disease, the most obvious symptomsare movement-related; these include shaking, rigidity, slowness ofmovement and difficulty with walking and gait. Later, thinking andbehavioral problems may arise, with dementia commonly occurring in theadvanced stages of the disease, whereas depression is the most commonpsychiatric symptom. Other symptoms include sensory, sleep and emotionalproblems. Parkinson's disease is more common in older people, with mostcases occurring after the age of 50; when it is seen in young adults, itis called young onset Parkinson's Disease.

The main motor symptoms are collectively called parkinsonism, or a“parkinsonian syndrome.” The disease can be either primary or secondary.Primary Parkinson's disease is referred to as idiopathic (having noknown cause), although some atypical cases have a genetic origin, whilesecondary parkinsonism is due to known causes, e.g., toxins. Many risksand protective factors have been investigated: the clearest evidence isan increased risk of Parkinson's in people exposed to certain pesticidesand a reduced risk in tobacco smokers. The pathology of the disease ischaracterized by the accumulation of protein in neurons (Lewy bodies),and from insufficient formation and activity of dopamine in certainparts of the midbrain. The location of the Lewy bodies is often relatedto the expression and degree of the symptoms of an individual. Diagnosisof typical cases is mainly based on symptoms, with tests such asneuroimaging used for confirmation.

A cohort of 60 patients with Parkinson's disease between the ages of40-65 years of age is identified by both a neurologist andneuropsychiatrist. A detailed motor, cognitive, and general neurologicalexamination is paramount, complete with the use of standardized motorstatus scales, mental status scales, in particular, the Mini-MentalStatus Examination (MMSE), to document the progression of Parkinson'sand the Montreal Cognitive Assessment (MoCA) owing to its superiorsensitivity in detecting mild cognitive impairment and increasedsensitivity to executive and language dysfunction. A neurophyschologicalassessment will establish a baseline in order to follow the patient overtime.

The experimental group patients (n=20; “EXPT1”) receives levocetirizineand montelukast once a day. The experimental group patients (n=20;“EXPT2) receives levocetirizine and montelukast twice a day. The controlgroup patients (n=20; “CONT”) receive a placebo.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history, and previous surgery arelogged at the initial visit and the patient's overall status trackedmonthly over one year.

Additional specimens are drawn for analysis, which include: [0445]

Serum levels of levocetirizine and montelukast monthly;

Sample for NF-kB, initially and at the conclusion of the study;

Samples for chemokines, cytokines, and biomarkers of inflammation at thetime of entry into the study and at completion (52 weeks). These includebut are not limited to: Granulocyte macrophage colony stimulating factor(GM-CSF); GROα; Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin12p70 (IL-12p70); IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptorantagonist (IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducibleprotein 10 (IP-10); Monocyte chemoattractant protein 1 (MCP-1);Macrophage colony stimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40ligand (sCD40L); Soluble E-selectin (sE-selectin); Soluble Fas ligand(sFasL); Tumor necrosis factor α (TNF-α); Serum amyloid antigen (SAA);regulated on activation, normal T-cell expressed and secreted (RANTES);Cortisol; CSF for molecular biomarkers of Aβ protein deposition: CSFAβ42, total tau and phosphor-tau initially and at the completion of thestudy.

Imaging: MRI of the brain

Dosing

-   “EXPT1”—levocetirizine 5 mg, orally at night, montelukast 10 mg    orally at night-   “EXPT2”—levocetirizine: 2.5 mg orally in the morning and 5.0 mg    orally at night plus montelukast: 5 mg orally in the morning and 10    mg orally at night-   “CONT”—placebo

Outcome

The clinical course, as measured by the MMSE and Clinical DementiaRating Scale is not necessarily linear, however, a number of studieshave found that patients decline 3 to 3.5 points on the average on theMMS capital E each year, with a minority (<10%) having a more rapidlyprogressive decline of 5 to 6 points on annual MMSE. Standardized motortesting is also performed.

Patients receiving the levocetirizine and montelukast (EXPT1 and EXPT2)remain at baseline or deteriorate more slowly the control group (CONT),based on multiple scales of clinical efficacy (cognitive and motor).Patient receiving bid dosing of levocetirizine and montelukast (EXPT2)remain at baseline or deteriorate even more slowly than the group dosedonce per day (EXPT1) or (CONT), based on multiple scales of clinicalefficacy. The EXPT1 group declines at 15% the rate of the CONT group(both cognitively and for motor function) and the EXPT2 group declinesat 5% the rate of the CONT group (both cognitively and for motorfunction).

Both (EXPT1) and (EXPT2) have a lower dropout rate than the controlgroup, (CONT) (a dropout rate that is 30% and 20% of that of the CONTgroup for EXPT1 and EXPT2, respectively)

In summary, levocetirizine and montelukast significantly decreases therate of clinical deterioration when administered to a group ofParkinson's patients over one year.

Example 13 Huntington's Disease

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

Huntington's disease (HD) is a neurodegenerative genetic disorder thataffects muscle coordination and leads to mental decline and behavioralsymptoms. Symptoms of the disease can vary between individuals andaffected members of the same family, but usually progress predictably.The earliest symptoms are often subtle problems with mood or cognition.A general lack of coordination and an unsteady gait often follows. Asthe disease advances, uncoordinated, jerky body movements become moreapparent, along with a decline in mental abilities and behavioralsymptoms. Physical abilities gradually worsen until coordinated movementbecomes difficult. Mental abilities generally decline into dementia.Complications such as pneumonia, heart disease, and physical injury fromfalls reduce life expectancy to around twenty years from the point atwhich symptoms begin. Physical symptoms can begin at any age frominfancy to old age, but usually begin between 35 and 44 years of age.The disease may develop earlier in life in each successive generation.About 6% of cases start before the age of 21 years with anakinetic-rigid syndrome; they progress faster and vary slightly. Thevariant is classified as juvenile, akinetic-rigid, or Westphal variantHD.

A cohort of 60 patients with Huntington's disease between the ages of30-45 years of age is identified by both a neurologist andneuropsychiatrist. A detailed motor, cognitive, and general neurologicalexamination is paramount, complete with the use of standardized motorand mental status testing. A motor, muscular, and neurophyschologicalassessment will establish a baseline in order to follow the patient overtime.

The experimental group patients (n=20; “EXPT1”) receives levocetirizineand montelukast once a day. The experimental group patients (n=20;“EXPT2) receives levocetirizine and montelukast twice a day. The controlgroup patients (n=20; “CONT”) receive a placebo.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history, and previous surgery arelogged at the initial visit and the patient's overall status trackedmonthly over one year.

Additional specimens are drawn for analysis, which include:

Genetic molecular testing for HD [0458] Serum levels of levocetirizineand montelukast monthly;

Sample for NF-kB, initially and at the conclusion of the study;

Samples for chemokines, cytokines, and biomarkers of inflammation at thetime of entry into the study and at completion (52 weeks). These includebut are not limited to: Granulocyte macrophage colony stimulating factor(GM-CSF); GROα; Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin12p70 (IL-12p70); IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptorantagonist (IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducibleprotein 10 (IP-10); Monocyte chemoattractant protein 1 (MCP-1);Macrophage colony stimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40ligand (sCD40L); Soluble E-selectin (sE-selectin); Soluble Fas ligand(sFasL); Tumor necrosis factor α (TNF-α); Serum amyloid antigen (SAA);regulated on activation, normal T-cell expressed and secreted (RANTES);Cortisol;

Imaging: MRI of the brain

Dosing

-   “EXPT1”—levocetirizine 5 mg, orally at night, montelukast 10 mg    orally at night-   “EXPT2”—levocetirizine: 2.5 mg orally in the morning and 5.0 mg    orally at night plus montelukast: 5 mg orally in the morning and 10    mg orally at night-   “CONT”—placebo

Outcome

Patients receiving the levocetirizine and montelukast (EXPT1 and EXPT2)remain at baseline or deteriorate more slowly the control group (CONT),based on multiple scales of clinical efficacy (both cognitive andmotor). Patient receiving bid dosing of levocetirizine and montelukast(EXPT2) remain at baseline or deteriorate even more slowly than thegroup dosed once per day (EXPT1) or (CONT), based on multiple scales ofclinical efficacy (both cognitive and motor). The EXPT1 group declinesat 25% the rate of the CONT group (both cognitively and for motorfunction) and the EXPT2 group declines at 20% the rate of the CONT group(both cognitively and for motor function).

Both (EXPT1) and (EXPT2) have a lower dropout rate than the controlgroup, (CONT) (a dropout rate that is 30% and 20% of that of the CONTgroup for EXPT1 and EXPT2, respectively)

In summary, levocetirizine and montelukast significantly decreases therate of clinical deterioration when administered to a group ofHuntington's patients over one year.

Example 14 Amyotrophic Lateral Sclerosis (ALS)

Based on the inventor's clinical experience using levocetirizine andmontelukast, the following results are projected using controlledstudies.

Amyotrophic lateral sclerosis (ALS) is a disorder that involves thedeath of neurons. ALS is characterized by stiff muscles, muscletwitching, and gradually worsening weakness due to muscle wasting. Thisresults in difficulty speaking, swallowing, and eventually breathing.About 5-10% of cases are inherited from a person's parents. About halfof these genetic cases are due to one of two specific genes. Recently,ALS has been correlated with repeated head injury with resultant deathof the neurons that control voluntary muscles. The diagnosis is based ona person's signs and symptoms with testing done to rule out otherpotential causes.

The disease usually starts around the age of 60 and in inherited casesaround the age of 50. The average survival from onset to death is threeto four years. About 10% survive longer than 10 years. Most die fromrespiratory failure.

A cohort of 60 patients with ALS between the ages of 45 and 60 years ofage is identified by both a physician. A detailed motor and generalneurological examination is paramount, complete with the use ofstandardized motor testing (e.g., EMG—electromyogram and nerveconduction studies), to document the progression of ALS. Thisestablishes a patient baseline.

The experimental group patients (n=20; “EXPT1”) receives levocetirizineand montelukast once a day. The experimental group patients (n=20;“EXPT2) receives levocetirizine and montelukast twice a day. The controlgroup patients (n=20; “CONT”) receive a placebo.

Age, sex, race, height, weight, BMI (Body Mass Index/kg/m²), vitalsigns, major medical problems, medications, allergies to medications,cigarette and alcohol use, social history, and previous surgery arelogged at the initial visit and the patient's overall status trackedmonthly over one year.

Additional specimens are drawn for analysis, which include:

Serum levels of levocetirizine and montelukast monthly;

Sample for NF-kB, initially and at the conclusion of the study;

Samples for chemokines, cytokines, and biomarkers of inflammation at thetime of entry into the study and at completion (52 weeks). These includebut are not limited to: Granulocyte macrophage colony stimulating factor(GM-CSF); GROα; Interferon α2 (IFNα2); IFNβ; IFNγ; IL-10; Interleukin12p70 (IL-12p70); IL12p40; Interleukin 1α (IL-1α); IL-1β; IL-1 receptorantagonist (IL-1RA); IL-2; IL-4; IL-5; IL-6; IL-8; IFN-γ-inducibleprotein 10 (IP-10); Monocyte chemoattractant protein 1 (MCP-1);Macrophage colony stimulating factor (MCSF); MIP-α; MIP-1β; Soluble CD40ligand (sCD40L); Soluble E-selectin (sE-selectin); Soluble Fas ligand(sFasL); Tumor necrosis factor α (TNF-α); Serum amyloid antigen (SAA);regulated on activation, normal T-cell expressed and secreted (RANTES);Cortisol.

Imaging: MRI of the brain

Dosing

-   “EXPT1”—levocetirizine 5 mg, orally at night, montelukast 10 mg    orally at night-   “EXPT2”—levocetirizine: 2.5 mg orally in the morning and 5.0 mg    orally at night plus montelukast: 5 mg orally in the morning and 10    mg orally at night-   “CONT”—placebo

Outcome

Patients receiving the levocetirizine and montelukast (EXPT1 and EXPT2)remain at baseline or deteriorate more slowly the control group (CONT),based on multiple scales of clinical efficacy and electrodiagnostictesting. Patient receiving bid dosing of levocetirizine and montelukast(EXPT2) remain at baseline or deteriorate even more slowly than thegroup dosed once per day (EXPT1) or (CONT), based on multiple scales ofclinical efficacy and electrodiagnostic testing. The EXPT1 groupdeclines at 25% the rate of the CONT group (clinical andelectodiagnostic testing) and the EXPT2 group declines at 20% the rateof the CONT group (clinical and electrodiagnostic testing).

Both (EXPT1) and (EXPT2) have a lower dropout rate than the controlgroup, (CONT) (a dropout rate that is 30% and 20% of that of the CONTgroup for EXPT1 and EXPT2, respectively)

In summary, levocetirizine and montelukast significantly decreases therate of clinical deterioration when administered to a group of ALSpatients over one year.

What is claimed is:
 1. A method of treating a patient having an NFκB-mediated condition, the method comprising administering to the patient an effective amount of a combination of levocetirizine and montelukast.
 2. The method of claim 1, wherein the condition is a neurological disease.
 3. The method of claim 1, wherein the condition is selected from the group consisting of Alzheimer's disease, dementia, dementia with Lewy bodies, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington's disease.
 4. The method of claim 1, wherein the condition is caused by a viral infection.
 5. The method of claim 1, wherein the condition is caused by a virus selected from the group consisting of the Ebola virus, the West Nile virus, the Yellow Fever virus, the Dengue virus, the tick-borne-encephalitis virus, and HIV.
 6. The method of claim 1, wherein the combination of levocetirizine and montelukast is administered in a sequential manner.
 7. The method of claim 1, wherein the combination of levocetirizine and montelukast is administered in a substantially simultaneous manner.
 8. The method of claim 1, wherein the combination is administered to the patient by one or more of the routes consisting of enteral, intravenous, intraperitoneal, inhalation, intramuscular, subcutaneous and oral.
 9. The method of claim 1, wherein the levocetirizine and montelukast are administered by the same route.
 10. The method of claim 1, wherein the levocetirizine and montelukast are administered via different routes.
 11. The method of claim 1, wherein one or more of levocetirizine or montelukast are provided as a slow release composition.
 12. The method of claim 3, wherein the combination further comprises other medications known for use in treating one of the listed conditions.
 13. The method of claim 5, wherein the combination further comprises other medications known for use in treating one of the listed viruses.
 14. The method of claim 1, wherein the combination further comprises a steroid.
 15. A combination of levocetirizine and montelukast for use in the treatment of a viral infection.
 16. The combination of claim 15, wherein the viral infection is selected from Ebola virus, Yellow fever virus, West Nile virus, Dengue virus, tick borne-encephalitis or HIV.
 17. A combination of levocetirizine and montelukast for use in the treatment of a neurodegenerative disease.
 18. The combination of claim 17, wherein the neurodegenerative disease is selected from Alzheimer's disease, dementia, dementia with Lewy bodies, Parkinson's disease, amyotrophic lateral sclerosis, frontotemporal dementia or Huntington's disease. 